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CONTENTSMessage from the Chair .................................................. 4

The University of Notre Dame ....................................... 5

The Department of Chemistry and Biochemistry ........... 6

Research Facilities .......................................................... 6

Affiliated Research Centers ............................................ 7

The Graduate Program .................................................... 8

Financial Support ............................................................ 8

Application Process ........................................................ 9

Housing ........................................................................... 9

Faculty Research Interests .......................................14-60

Brandon Ashfeld

Brian M. Baker

Paul Bohn

Jessica Brown

Seth N. Brown

Jon Camden

Ian Carmichael

Francis J. Castellino

Patricia L. Clark

Steven Corcelli

Norman Dovichi

Haifeng Gao

J. Daniel Gezelter

Holly Goodson

Gregory V. Hartland

Paul Helquist

Paul W. Huber

Amanda B. Hummon

Vlad M. Iluc

Prashant Kamat

S. Alex Kandel

Masaru K. Kuno

A. Graham Lappin

Marya Lieberman

Laurie Littlepage

Shahriar Mobashery

John Parkhill

Jeffrey W. Peng

Zachary Schultz

Anthony S. Serianni

Slavi C. Sevov

Bradley D. Smith

Sharon Stack

Rich Taylor

Emily Tsui

Olaf Wiest

Energy

Life Processes

Materials

Measurement

Medicine

Sythesis

Theory

Research SpecialtiesTenured and Tenure-Track Faculty

Concurrent FacultyDave Bartels

Başar Bilgiçer

Peter C. Burns

William Schneider

Aaron Timperman

Research Faculty

Adjunct Faculty

Mayland Chang

Victoria Ploplis

Sergei Vakulenko

Karen Cowden Dahl

Margaret Schwarz

Robert Stahelin

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The 1,250-acre campus of the University of Notre Dame is located on the north side of South Bend,

Ind., just 90 miles from Chicago. Founded in 1842 by Rev. Edward F. Sorin, a French Holy Cross priest, Notre Dame had very humble beginnings. Now, it is the preeminent Catholic educational institution in the United States, with an annual enrollment of more than 11,400 graduate and undergraduate students, and more than 1,100 professors, who together hold advanced degrees from major universities around the world. Notre Dame’s endowment is the 12th largest in the country, and research in science attracts more than $40 million in federal research funds each year.

THE UNIVERSITY OF NOTRE DAME

MESSAGE

FROM THE CHAIRThank you for your interest in the Department of Chemistry and Biochemistry at the University of Notre Dame! This brochure provides an overview of the department and the research of our faculty. We have major strengths in all areas of modern chemistry and biochemistry and are deeply involved in interdisciplinary research. We have specialized concentrations in nanotechnology, materials chemistry, supramolecular chemistry, computational chemistry, analytical chemistry, and molecular biophysics. The presence of chemistry and biochemistry in one department is a significant advantage, and provides for state of the art research in chemical biology, the detection of disease, the discovery of new drugs, and the development of new molecular-based therapies.

Because of the interdisciplinary nature of our research, our faculty collaborate closely with other researchers across the university, such as those in the departments of biological sciences, physics, and chemical and biomolecular engineering. These efforts are supported by collaborative centers on campus with research missions that depend critically on the chemical and biochemical sciences.

We strive to provide our research and training programs with the best facilities and take pride in our modern research laboratories, state of the art instrumentation, and outstanding support personnel.

Graduate students are fundamental to all of the department’s research endeavors. After graduation, future success is typically found in academia, research institutions, and private industry. At the University of Notre Dame, our chemistry and biochemistry graduates are an investment in the future. We would be thrilled to have you join us. Sincerely,

Brian M. BakerRev. John A. Zahm Professor and Chair, Department of Chemistry and Biochemistry

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THE DEPARTMENT OF

CHEMISTRY ANDBIOCHEMISTRY

The graduate program in chemistry and biochemistry at Notre Dame has experienced a period of sustained growth over the last decade through

the support of the University and the endeavors of our internationally recognized faculty. On a yearly basis, the department regularly supports approximately 180 graduate students and 50 postdoctoral fellows and receives external research funding in excess of $9 million. This places the department consistently within the top 20 federally funded research programs in the country.

Our research laboratories are primarily in two adjoining buildings, Nieuwland Science Hall and the Stepan Hall of Chemistry and Biochemistry. This summer several of our investigators moved to the newly completed McCourtney Hall, a multidisciplinary research building housing 100,000 square feet of laboratory space and an abundance of collaborative and team spaces.

Along with the Jordan Hall of Science, one of the premier instructional science buildings in the country, the research and teaching facilities available to the department have nearly tripled over the past 10 years.

RESEARCH FACILITIESGenomics & Bioinformatics Core Facility can accommodate a range of sequencing and expression analyses. The facility operates three microarray platforms for analysis of transcripts from various tissue types and gDNA genotyping and comparative genome hybridiza-tion. genomics.nd.edu

Magnetic Resonance Research Center houses the following array of FT-NMR spectrometers: an 800 MHz, a 700 MHz, a 600 MHz, three 500 MHz, two 400 MHz, and a 300 MHz (solid-state). All of the spec-trometers are multinuclear and a large variety of probes are available. nmr.nd.edu

Mass Spectrometry and Proteomics Facility provides instrumentation and expertise for the analyses of compounds ranging from small organic mole-cules to large biomolecules with applications in the areas of metabolomics, proteomics, and lipidomics. massspec.nd.edu

Materials Characterization Facility offers a diverse range of instrumentation, including FTIR and UV-Vis-NIR spectrometers, Raman microscopy, X-ray photoelectron spectrometry, and differential scanning calorimetry. mcf.nd.edu

Molecular Structure Facility houses three state-of-the-art X-ray diffractometers, which are used for routine low-temperature analysis of single crystal and powder samples. The facility is open to all of our graduate stu-dents who have the opportunity to perform all aspects of their crystallography experiments. xray.nd.edu

Notre Dame Integrated Imaging Facility is a state-of-the-art research core that provides an integrated suite of sophisticated microscopes and imaging stations that enable researchers to attack the most complex, mod-ern research problems. Microscopic and biological imag-ing are among the most common experimental techniques employed by science and engineering researchers at the University of Notre Dame. ndiif.nd.edu

Chemical Synthesis and Drug Discovery (CSDD) Facility supports translational biomedical re-search by providing expertise in the preparation of small molecules for use in hit verification, lead development, and as biological probes. The CSDD also oversees the Notre Dame Chemical Compound Collection, which contains more than 20,000 unique chemical entities. drugdiscovery.nd.edu

AFFILIATED RESEARCH CENTERS

Not only does the department make use of its own excellent research facilities, it also enjoys collaborative research opportunities with

departments across engineering and science disciplines in a number of affiliated research centers.

W. M. Keck Center for Transgene ResearchThe Keck Center was established in 1995 and utilizes more than 50 different strains of mice, top interdisci-plinary expertise, and the most advanced equipment to address an area of investigation that is at the forefront of medical research: hemostasis. transgene.nd.edu

Radiation LaboratoryThe Notre Dame Radiation Laboratory, a joint venture of the University of Notre Dame and the U.S. Depart-ment of Energy, is an international center advancing the understanding of the interaction of radiation (both light and ionizing) with matter. rad.nd.edu

Center for Sustainable Energy at Notre Dame (ND Energy) ND Energy brings together researchers to address the global challenges of a more sustainable energy future, emphasizing approaches to transformative solar, clean-er fossil, and safer nuclear power. energy.nd.edu

Center for Environmental Science and Technology (CEST)CEST is a cooperative effort between Notre Dame’s colleges of science and engineering, fostering inter-disciplinary environmental research and education by providing cutting-edge analytical technologies needed to address complex environmental problems. cest.nd.edu

Harper Cancer Research InstituteResearchers in the Harper Cancer Research Institute are exploring the genetic basis of colon, prostate, breast, and ovarian cancers with unique animal models de-veloped in the research center. Results of these studies may provide the basis for understanding the origin of these diseases as well as provide molecular targets for the development of new drugs and other treatments. harpercancer.nd.edu

Center for Nano Science and TechnologyResearchers in this center explore new device concepts and associated architectures enabled by novel phenom-ena on the nanometer scale. The center catalyzes multi-disciplinary research and education in nanoelectronics, molecular electronics, nano-bio and bio-fluidic micro-structures, circuits, and architectures. nano.nd.edu

Advanced Diagnostics & Therapeutics This center is a community of affiliated researchers who tackle a wide range of biomedical and environmen-tal health problems - such as sepsis, cancer, influenza, wound healing, drug addiction, mosquito-borne diseas-es, autism, cystic fibrosis, air pollution, invasive species, and many others - through innovation, invention, and real-world applications. advanceddiagnostics.nd.edu

Center for Research ComputingThis University resource provides state-of-the-art, high-end computing, communications infrastructure, and software as well as skilled technical computing staff. crc.nd.edu

Warren Family Research Center for Drug Discovery and DevelopmentThe Warren Center is a resource for a highly productive and renowned group of drug discovery faculty with expertise and interest in areas such as neurological and central nervous system disorders, infectious disease, cancer, and rare diseases. drugdiscovery.nd.edu

McCourtney Hall

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As you work toward your degree …The department puts a great deal of emphasis on securing the best possible placement of our students prior to graduation. To achieve this, we have an in-house recruitment program and work closely with the professional development arm of the Graduate School to help students plot the path and trajectory of their career. For more information visit graduateschool.nd.edu/professional_development.

FINANCIAL SUPPORTAll first-year students are supported as teaching assistants during the academic year and receive a competitive stipend, a full-tuition scholarship and a summer research appointment. After the first year, students are supported as teaching or research assistants either through University support or by their faculty mentor through external research awards.

Our 12-month stipend is competitive with other institutions in the region, although the cost of living near Notre Dame is very affordable. This means that our students typically enjoy a higher standard of living than graduate students at other institutions. University and departmental fellowships are also available on a competitive basis. In particular, the Chemistry-Biochemistry-Biology Interface (CBBI) Program at Notre Dame is an NIH-funded program designed to train predoctoral students at the interface of chemistry, biochemistry, and biology. Students conducting research in CBBI laboratories are eligible for support by a training grant from the National Institutes of Health.

THE GRADUATE PROGRAMOur department is characterized by an unsurpassed commitment to the development of our graduate students into well-rounded individuals who can take on leadership roles in industry, academia, or government upon graduation. Notre Dame graduate students enjoy all the benefits of attending a world-class university consistently ranked among the 20 best in the nation: outstanding facilities, great faculty, and a stimulating group of fellow students from all over the United States and the world. The fact that Notre Dame is a smaller private university, however, means that our graduate students don’t get lost in the shuffle. With about 180 graduate students and 46 faculty, you will receive individualized attention from your advisor and form close bonds with the other graduate students in the department. The research, coursework, and teaching experience gained during the doctoral program provide our students with the tools necessary to succeed after graduation.

We invite you to explore the pages describing the research going on in the department. Please contact us if you have any questions about the program or the application process.

APPLICATION PROCESSTo apply to our graduate programs in chemistry and biochemistry, visit our online application at https://gradconnect.nd.edu/apply/.Domestic U.S. students and permanent residents may apply free of charge.

HOUSINGThe University of Notre Dame has a limited number of single and multiple-occupancy rooms and apartments available on campus. Also note that the housing costs in the South Bend region are among the lowest in the nation. For more information, visit the website for the Office of Residential Life and Housing at housing.nd.edu/graduate.

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RECREATIONThe recreational facilities on campus are extensive, with an ice rink, several basketball courts, handball/racquetball courts, squash courts, and an Olympic-size pool in the Joyce Center alone. Two golf courses; a recreational sports center, including a ⅛-mile, suspended running track; a pavilion with six indoor tennis courts (to complement the 24 outdoor courts); and numerous other venues for sports provide for the physical activities so important to students. The department also has several different intramural sports teams.

THE ARTSCultural events are important at Notre Dame. The Snite Museum of Art is home to five galleries and more than 17,000 items, and the magnificent DeBartolo Performing Arts Center hosts everything from movies to symphonic orchestras to international performers, all here on the Notre Dame campus.

NOTRE DAME FOOTBALLNotre Dame fields 26 varsity athletic teams, with the football team being the most famous, hosting more than 80,000 fans per game each fall. Every student has the opportunity to purchase tickets for all campus sporting events.

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BRANDON L. ASHFELDAssociate Professor

Director of Graduate Studies(574) 631-1727 [email protected]

BRIAN M. BAKERRev. John A. Zahm ProfessorDepartment Chair(574) 631-9810 [email protected]

Ruth L. Kirschstein National Institute of HealthPostdoctoral fellow, Stanford University, 2004–07PhD, Chemistry, University of Texas at Austin, 2004BS, Chemistry, University of Minnesota, 1998

Synthetic Organic Chemistry

Our research interests lie in the development of new methods for the synthesis of complex natural products and designed materials. Our main objective is to use new chemical constructs to design and synthesize improved chemotherapies for brain and CNS cancers and materials that will ultimately lead to the reduction of atmospheric concentrations of anthropogenic CO2.

One area our program seeks to address is the issue of suitable brain and nervous system cancer drug treatments by evaluating diarylheptanoids bearing promising cytotoxicity and blood brain barrier (BBB) transcytosis properties. We are currently working toward the development of two new synthetic methods that will enable the efficient and scalable construction of these natural products. The first approach is based on the conceptual design of a tandem reaction sequence composed of mechanistically distinct transformations facilitated by a single catalyst to rapidly assemble all alkyl-substituted tertiary carbons centers. Our second area focuses on the formation of Csp2–N and Csp2–C bonds through the development of phosphorus-mediated C–C and C–N bond formations that ultimately circumvents the need for traditional organometallic or transition metal-based reagents.

Managing the impact of human activities on the concentration of CO2 in the atmosphere is the most far-reaching environmental challenge facing the world today. Our ultimate goal is the development of a regenerative material that will undergo selective super-stoichiometric carbon capture with near-zero parasitic energy consumption. Recognizing that C–C and C–X chemical bonds are convenient media for energy storage, transport, and consumption, our efforts rely on the design and synthesis of functionalized N-heterocyclic anions and carbenes for energy efficient gas phase removal of CO2.

Honors and Awards

National Science Foundation CAREER Award, 2011University of Notre Dame Faculty Scholarship Award, 2009Ruth L. Kirschstein National Postdoctoral Fellowship Award,

2004-2007

Selected Publications

Wilson, E.E.; Rodriguez, K.X.; Ashfeld, B.L. “Stereochemical implications in the synthesis of 3,3’-spirocyclopropyl oxindoles from beta-aryl/alkyl-substituted alkylidene oxindoles.” Tetrahedron 2015, 71(53), 5765-5775.

Haugen, K.C.; Rodriguez, K.X.; Chavannavar, A.P.; Oliver, A.G.; Ashfeld, B.L. “Phosphine-mediated addition of 1,2-dicarbonyls to diazenes: an umpolung approach toward N-acyl hydrazone synthesis.” Tetrahedron Lett.2015, 56(23), 3527-3530.

Gianino, J.B.; Campos, C.A.; Lepore, A.J.; Pinkerton, D.M.; Ashfeld, B.L. “Redox and Lewis Acid Relay Catalysis: A Titanocene/Zinc Catalytic Platform in the Development of Multicomponent Coupling Reactions.” J. Org. Chem. 2014, 79(24), 12083-12095.

Chavannavar, A.P.; Oliver, A.G.; Ashfeld, B.L. “An umpolung approach toward N-aryl nitrone construction: a phosphine-mediated addition of 1,2-dicarboyls to nitroso electophiles.” Chem. Commun. 2014, 50 (74), 10854-10856.

Meloche, J.L.; Vednor, P.T.; Gianino, J.B.; Oliver, A.G.; Ashfeld, B.L. “Titanocene-catalyzed metallation of propargylic acetates in homopropargyl alcohol synthesis.” Tetrahedron Lett. 2014, 55 (36), 5025-5028.

Fleury, L. M.; Wilson, E. E.; Vogt, M.; Fan, T. J.; Oliver, A. G.; Ashfeld, B. L. “An Amine-Free Approach Toward N-Toluenesulfonyl Amidine Construction: A Phosphite-Mediated Beckmann-Like Ligation of Oximes and Azides.”Angew. Chem. Int. Ed. 2013, 52 (44), 11589-11593.

Postdoctoral fellow, Harvard University, 1998–2001PhD, Biochemistry, University of Iowa, 1997BS, Biochemistry, New Mexico State University, 1992

Biophysics and Structural Biology of Molecular Recognition and Cellular Communication

How do biological molecules specifically recognize targets, how does recognition lead to cellular communication, and how do the physical aspects of these processes give rise to biological function? Baker studies these broad areas utilizing a diverse array of structural, biophysical, biochemical, and biological approaches. The work emphasizes molecular recognition, communication, and function in the general areas of cellular immunity and bacterial antibiotic resistance. Techniques used in the laboratory include solution biophysics, protein crystallography and NMR, mass spectrometry, computational biochemistry, and biological experiments with cell and animal models.

Much of the work focuses on the basis for antigen recognition in cellular immunity. The goal of this research is to understand how T cells of the immune system are able to specifically recognize some antigenic ligands, yet avoid others. The laboratory focuses on the T cell receptor and its ligand, small peptides bound and “presented” by major histocompatibility complex proteins, asking how structures, flexibilities, and chemical features give rise to recognition behavior. Beyond helping to understand the basic biochemistry of molecular recognition, these studies have implications for the functioning of the immune system, the immune response to cancer and infectious disease, and autoimmunity.

Another main project in the laboratory is the physical basis for T cell signaling. The T cell receptor complex on the surface of a T cell is a large, multi-protein supramolecular assembly. The laboratory aims to understand how this assembly is able to communicate the presence of a ligand to the interior of a cell. Utilizing basic principles of allosteric communication, the laboratory is exploring the idea that alterations in flexibility contribute to architectural changes on the outside of the cell that alter the positions of signaling modules on the inside of the cell. An important goal of this project is to determine the three-dimensional structure of the T cell receptor complex on the surface of a living cell, which will directly relate structural and physical properties to biology.

In partnership with computational biologists and immunologists, the laboratory is engineering immune receptors to target antigens presented by cancer cells with enhanced affinity, working towards strengthening the immune response to cancer. In the context of this

work, together with collaborators the laboratory is generating mice with genetically engineered immune systems that specifically target cancer. In a related project, the laboratory is working with medicinal chemists to design new vaccine candidates based on cellular immunity.

The laboratory also studies the evolution of bacterial antibiotic resistance, a significant threat to public health. Bacteria sense the presence of antibiotics via a “sensor” protein on the cell surface. Recognition of an antibiotic is communicated into the cell, leading to upregulation of the resistance machinery. The laboratory is studying how these sensor proteins evolved from machinery utilized in cell wall biosynthesis and how small structural differences give rise to significant changes in biological function. Taking cues from the work in the immune system, the laboratory is asking how recognition of an antibiotic by the sensor is communicated from the outside of the cell to the inside, with the long term goal of disrupting this process for the development of novel classes of antibiotics.

Awards

Rev. Edmund P. Joyce C.S.C Award for Excellence in Undergraduate Teaching, 2014

Director of Graduate Studies Award, 2012Research Scholar of the American Cancer Society, 2005NSF CAREER Award, 2005Fellow of the Cancer Research Institute, 1998-2001


Harris, D.T.; Singh, N.K.; Cai, Q.; Smith, S.N.; Vander Hooi, C.; Procko, E.; Kranz, D.M.; Baker, B.M. “An engineered switch in T cell receptor specificity leads to an unusual but functional binding geometry.” Structure 2016, 24(7), 1142-1154.

Ayres, C.M.; Scott, D.R.; Corcelli, S.A.; Baker, B.M. “Differential utilization of binding loop flexibility in T cell receptor ligand selection and cross-reactivity.” Sci. Reports 2016, 6, 25070.

Riley, T.P.; Singh, N.K.; Pierce, B.G.; Weng, Z.; Baker, B.M. “Computational modeling of TCR-pMHC complexes.”Methods Mol. Biol. 2016, 1414, 319-340.

Blevins, S.J.; Pierce, B.G.; Singh, N.K.; Riley, T.P.; Wang, Y.; Spear, T.T.; Nishimura, M.I.; Weng, Z.; Baker, B.M. “How structural adaptability exists alongside HLA-A2 bias in the humanαβ TCR repertoire.” P. Natl. Acad. Sci. USA 2016, 113(9), E1276-E1285.

chemistry.nd.edu chemistry.nd.edu

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DAVID M. BARTELSConcurrent Professor

(574) [email protected]

BAŞAR BILGIÇERConcurrent Associate Professor(574) 631-1429 [email protected]

Postdoctoral fellow, Brown University, 1982–85PhD, Chemistry, Northwestern University, 1982BS, Chemistry, Hope College, 1977

Radiation Chemistry and Photochemistry of Water

Ionizing radiation plays a major role in many modern chemical technologies involving polymerization and sterilization. It plays a decisive role in nuclear power plants and interstellar chemistry. The initial ionization event separates charges and spin, forming ions and free radicals whose subsequent reactions dominate the chemistry. The Bartels group uses multiple experimental and theoretical tools to quantify and understand the free radical reactions. These include electron pulse radiolysis with transient optical, conductivity, and electron paramagnetic resonance detection, and molecular dynamics simulations.

Recent work has focused on the free radical reactions in nuclear reactor cooling loops around 300°C to develop a comprehensive and accurate model of the chemistry. Hydrated electrons, hydrogen atoms, and OH radicals are formed as the dominant initial species, and each of these are very interesting from the point of view of fundamental physical chemistry. A major goal is understanding and modeling reactions of solvated electrons. Generation IV reactors are supposed to use supercritical water coolant up to 500°C, and the density-dependence of reaction rates in the near-critical region becomes of great practical importance. New work involves reactions of metal ion and metal oxide corrosion products, and direct microscopy measurements of irradiated oxide surfaces intended to define the mechanism(s) of radiation-enhanced corrosion.


Postdoctoral fellow, Harvard University, 2005–2008PhD, Chemistry, Tufts University, 2004BS, Chemistry, Bogazici University, Turkey, 1998

Biophysical Chemistry and Biomolecular Drug Design

Multivalent binding is the simultaneous interaction of multiple ligands present on one biological entity with multiple receptors on another. Multivalent interactions carry great importance in biology and are observed from viral infection to immune system surveillance of pathogens and cancer cells. Our group is interested in multivalency from two angles: 1) developing an improved understanding for the thermodynamics and kinetics of multivalent interactions; and 2) designing multivalentagents for diagnostic and therapeutic applications in cancers, autoimmune diseases, allergies, and HIV. We believe that a deeper understanding of the thermodynamics and kinetics of multivalent interactions in biological systems is imperative in the development of new diagnostic and therapeutic agents.

The research projects in our group are developed around the common theme of developing multivalent molecules for not just enhancing binding affinity, but also for providing selectivity in binding.

An example project for incorporation of multivalency in therapeutic molecular design application is reduction of non-specific toxicity associated with pharmaceutical antibodies by delivering them as bicyclic complexes. Currently, there are more than 30 pharmaceutical antibodies used worldwide in the treatment of a wide range of diseases including viral infection, cancer, and autoimmune diseases. Therapeutic antibodies rely on the high affinity interactions with a cell surface receptor that is overexpressed on cancer cells and has a lower expression profile or is supposedly non-existent on healthy cells. Non-specific toxicity, however, still remains a problem with therapeutic antibodies. We are currently developing a targeting strategy where we increase the selectivity of therapeutic antibodies for their target cells by delivering them as bicyclic complexes formed via interactions with corresponding synthetic trivalent ligands (Figure 1). The bicyclic complexes have a relatively low dissociation constant, which keeps the antibody molecules in the form of the complex. Therefore, only target cells with a high receptor density (as in the case of cancer cells) would be able to competitively dissociate the bicyclic complexes and recruit the antibodies to their surfaces, thereby providing improved selectivity for the therapeutic agent. We are currently collaborating with the pharmaceutical industry to develop a reduced-toxicity drug-delivery-system for an FDA approved antibody therapeutic.

The ultimate goal of our research program is to provide innovative therapeutic and diagnostic tools to improve patient outcomes.


Deak, P.E.; Vrabel, M.R.; Pizzuti, V.J.; Kiziltepe, T.; Bilgicer, B. “Nanoallergens: A multivalent platform for studying and evaluating potency of allergen epitopes in cellular degranulation.” Exp. Biol. Med. 2016, 241(9), 996-1006.

Mustafaoglu, N.; Alves, N.J.; Bilgicer, B. “Oriented Immobilization of Fab Fragments by Site-Specific Biotinylation at the Conserved Nucleotide Binding Site for Enhanced Antigen Detection.” Langmuir 2015, 31(35), 9728-9736.

Stefanick, J.F.; Kiziltepe, T.; Bilgicer, B. “Improved Peptide-Targeted Liposome Design Through Optimized Peptide Hydrophilicity, Ethylene Glycol Linker Length, and Peptide Density.” J. Biomed. Nanotechnol. 2015, 11(8), 1418-1430.

Mustafaoglu, N.; Alves, N.J.; Bilgicer, B. “Site-specific fab fragment biotinylation at the conserved nucleotide binding site for enhanced ebola detection.” Biotechnol. Bioeng. 2015, 112(7), 1327-1334.

Ashley, J.D.; Stefanick, J.F.; Schroeder, V.A.; Suckow, M.A.; Alves, N.J.; Suzuki, R.; Kikuchi, S.; Hideshima, T.; Anderson, K.C.; Kiziltepe, T.; Bilgicer, B. “Liposomal carfilzomib nanoparticles effectively target multiple myeloma cells and demonstrate enhanced efficacy in vivo.” J. Control. Release 2014, 196, 113-121.

Handlogten, M.W.; Deak, P.E.; Bilgicer, B. “Two-Allergen Model Reveals Complex Relationship between IgE Crosslinking and Degranulation.” Chem. Biol. 2014, 21(11), 1445-1451.


Kumar, A.; Walker, J. A.; Bartels, D. M.; Sevilla, M. D. A Simple ab Initio Model for the Hydrated Electron That Matches Experiment. The Journal of Physical Chemistry A 2015, 119, 9148-9159.

Kanjana, K.; Courtin, B.; MacConnell, A.; Bartels, D. M. Reactions of Hexa-aquo Transition Metal Ions with the Hydrated Electron up to 300 degrees C. J. Phys. Chem. A 2015, 119, 11094-11104.

Nuzhdin, K.; Bartels, D. M. Hyperfine coupling of the hydrogen atom in high temperature water. J. Chem. Phys. 2013, 138, 8.

Wu, W. Q.; Nuzhdin, K.; Vyushkova, M.; Janik, I.; Bartels, D. Comparison of Acid Generation in EUV Lithography Films of Poly(4-hydroxystyrene) (PHS) and Noria Adamantyl Ester (Noria-AD50). J. Phys. Chem. B 2012, 116, 6215-6224.

Hare, P. M.; Price, E. A.; Stanisky, C. M.; Janik, I.; Bartels, D. M. Solvated Electron Extinction Coefficient and Oscillator Strength in High Temperature Water. J. Phys. Chem. A 2010, 114, 1766-1775.

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PAUL W. BOHNArthur J. Schmitt Professor

Director, Advanced Diagnostics & Therapeutics(574) 631-1849

[email protected]

JESSICA A. BROWNAssistant Professor(574) [email protected]


American Cancer Society Postdoctoral Fellow, Yale University, 2012–2014

PhD, Biochemistry, The Ohio State University, 2010BS, Chemistry and Biological Sciences, Wright State

University, 2005

Structural, Biochemical & Cellular Roles of RNA Triple Helices

RNA structure is largely viewed as being single-stranded or double-stranded, although triple-stranded RNA structures were deduced to form in test tubes almost 60 years ago. Despite this early discovery, only four examples of RNA triple helices have been validated in eukaryotic cellular RNAs. The long-term goal of the Brown laboratory is to understand the structural, biochemical, and cellular roles of RNA triple helices using the MALAT1 triple helix as a model. This triple helix forms at the 3¢ end of the long noncoding RNA, MALAT1 (metastasis-associated lung adenocarcinoma transcript 1). This triple helix forms when a U-rich internal loop of a stem-loop structure binds and sequesters a downstream 3’-terminal A-rich tract. This unique triple-helical structure, composed of nine U•A-U triples separated by a C+•G-C triple and C-G doublet, protects MALAT1 from an uncharacterized rapid nuclear RNA pathway.

The fundamental structural and biochemical properties of RNA triple helices remain to be rigorously characterized. The Brown laboratory is interested in several key questions. Do proteins bind specifically to the MALAT1 triple helix? Is there an undiscovered class of triple-stranded RNA binding proteins? How does the cell degrade a highly stable triple-helical RNA structure? What is the relative stability of canonical (U•A-U and C•G-C) versus non-canonical base triples? Can successive non-canonical base triples form a stable triple helix? What are the structural parameters of an ideal RNA triple helix? What is the folding pathway of an RNA triple helix? What other RNA triple helices exist in mammalian cells? To investigate these questions, we are currently using a variety of approaches, including X-ray crystallography, cell-based assays, molecular biology, classical biochemistry, and high-throughout methods.

Studying the MALAT1 triple helix will advance our understanding of cancer. MALAT1 is upregulated in multiple types of cancer and promotes tumor growth by affecting proliferation, invasion, and metastasis. Importantly, the region of MALAT1 that is sufficient to induce oncogenic activities includes the triple helix. Our work shows that the MALAT1 triple helix is required for MALAT1 accumulation; therefore, we are currently

exploring whether the triple helix plays a direct role in mediating oncogenic activities beyond its function as an RNA stability element.

Awards

NIH Pathway to Independence Award (K99/R00), 2014-2019American Cancer Society Postdoctoral Fellowship, 2012-2014OSU Presidential Fellowship, 2010American Heart Association Predoctoral Fellowship, 2008-

2010


Brown, J.A.; Steitz, J.A. “Intronless ß-globin reporter: a tool for studying nuclear RNA stability elements.”Methods Mol. Biol. 2016, 1428, 77-92.

Brown, J.A.; Kinzig, C.G.; DeGregorio, S.J.; Steitz, J.A. “Hoogsteen-position pyrimidines promote the stability and function of the MALAT1 RNA triple helix.” RNA 2016, 22(5), 743-749.

Brown, J.A.; Bulkley, D.; Wang, J.; Valenstein, M.L.; Yario, T.A.; Steitz, T.A.; Steitz, J.A. “Structural Insights into the Stabilization of MALAT1 Noncoding RNA by a Bipartite Triple Helix.” Nat. Struct. Mol. Biol. 2014, 21(7), 633-640.

Brown, J.A.; Valenstein, M.L.; Yario, T.A.; Tycowski, K.T.; Steitz, J.A. “Formation of Triple-Helical Structures by the 3’-End Sequences of MALAT1 and MENβ Noncoding RNAs.” P. Natl. Acad. Sci. USA 2012, 109(47), 19202-19207.

Brown, J.A.; Pack, L.R.; Fowler, J.D.; Suo, Z. “Pre-Steady State Kinetic Investigation of the Incorporation of Anti-Hepatitis B Nucleotide Analogues Catalyzed by Non-Canonical Human DNA Polymerases.” Chem. Res. Toxicol.2012, 25, 225-233.

PhD, Chemistry, University of Wisconsin, 1981BS, Chemistry, University of Notre Dame, 1977

Molecular Nanoelectronics

Our group is interested in the active control of interfacial chemistry and morphology, as an entrée to developing nanoscale chemical devices for sensing, separations, and signal processing. Currently these interests are being explored in four main research thrusts in our group: (1) chemical sensors; (2) single molecule spectroelectrochemistry; (3) integrated microfluidics; and (4) chemical imaging.

Chemical Sensors. We study both conductance-based and plasmonic chemical sensors. The conductance sensors are based on adsorbate-induced surface wave-packet scattering as monitored in wires that, at their narrowest point, are only a single atom wide. This nanosensor is sensitive down to the detection of single molecules, and the sensing structure can be regenerated for multiple readout cycles. Plasmonic sensing takes advantage of second-generation plasmonic techniques employing either extraordinary optical transmission in sub-wavelength aperture arrays or phase-shift imaging to study problems in bioanalysis, such as strain-specific detection of infectious bacteria.

Single Molecule Spectroelectrochemistry. We utilize specialized nanophotonic structures, such as zero-mode waveguides, in order to isolate and study the behavior of single enzyme molecules. Currently, we are investigating FAD-bearing oxidases in which cycling through redox states results in a characteristic on-off emission pattern that allows us to watch single enzyme turnover events. We are working to couple these observations to Faradaic electron transfer events, thereby enabling the observation of single electron transfer events.

Integrated Microfluidics. We study 3D microfluidic structures in which vertically separated 2D fluidic layers communicate via fluidic devices that mimic the behavior of electronic diodes and transistors. Incorporating molecular recognition elements into these nanoscale structures permits intelligent nanofluidic control and opens the way to studies of controlled release and single-cell sampling. The key scientific questions here focus on how to selectively control transport over nanometer distances.

Chemical Imaging. Our chemical imaging projects focus on correlating image information across platforms, specifically Raman images acquired in our laboratory with SIMS and LDI

mass spectrometric images acquired by our collaborators. Putting together information from two complementary spectroscopic imaging probes allows us to obtain much more detailed information than would be available from either technique alone. At present, these approaches are being applied to problems in microbial communication and cancer biology.

Awards

Fellow, Society for Applied Spectroscopy, 2012Haines-Morris Lecturer, University of Tennessee, 2011Kritzler Lecturer, Ohio Northern University, 2011Theophilus Redwood Award, Royal Society of Chemistry, 2010Fellow, Royal Society of Chemistry, 2008


Ma, C.; Xu, W.; Wichert, W.R.A.; Bohn, P.W. “Ion Accumulation and Migration Effects on Redox Cycling in Nanopore Electrode Arrays at Low Ionic Strength,” ACS Nano 2016, 10, 3658-3664. [DOI 10.1021/acsnano.6b00049].

Zaino, L.P. III; Grismer, D.A.; Han, D.; Crouch, G.M.; Bohn, P.W. “Single Molecule Spectroelectrochemistry of Freely Diffusing Flavin Mononucleotide in Zero-Dimensional Nanophotonic Structures,” Faraday Disc. 2015, 184, 101-115. [DOI 10.1039/C5FD00072F]

Ma, C.; Zaino, L.P. III; Bohn, P.W. “Self-Induced Redox Cycling Coupled Luminescence on Nanopore Recessed Disk-Multiscale Bipolar Electrodes,” Chem. Sci. 2015, 6, 3173-3179. [DOI 10.1039/c5sc00433k]

Hwang, T.-W.; Bohn, P.W. “Potential-Dependent Restructuring and Chemical Noise at Au-Ag-Au Atomic Scale Junctions,” ACS Nano, 2014, 8, 1718-1727. [DOI 10.1021/nn06098u]

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SETH N. BROWNProfessor

(574) 631-4659 [email protected]

PETER C. BURNSConcurrent, Henry Massman Professor of Civil EngineeringDirector, Center for Sustainable Energy at Notre Dame(574) [email protected]


PhD, Geology, University of Manitoba, 1994MSc, Geology, University of Western Ontario, 1990 BSc, Geology, University of New Brunswick, 1988

Environmental and Actinide Chemistry

Burns’ research focuses on actinide chemistry and geochemistry, mostly involving uranium, neptunium, and thorium. Applications of the research include understanding transport of actinides in the environment, environmental remediation, nano-scale control of actinides to support an advanced nuclear energy system, the geologic disposal of nuclear waste, and nuclear forensics for national security. Central to the focus of the group is the synthesis and characterization of complex actinide materials in solution and the solid state using X-ray diffraction, X-ray scattering, and various spectroscopic techniques.

Awards

President of Mineralogical Association of Canada, 2008-2012 Vice president of the Mineralogical Association of Canada,

2006-2008Mineralogical Society of America Award and life fellow,

2001Donath Medal of the Geological Society of America, 1999Young Scientist Medal of the Mineralogical Association of

Canada, 1998Hawley Medal (best paper award) of the Mineralogical

Association of Canada, 1997

Publications

Qiu, J.; Dembowski, M.; Szymanowski, J.E.S.; Toh, W.C.; Burns, P.C. “Time-Resolved X-ray Scattering and Raman Spectroscopic Studies of Formation of a Uranium-Vanadium-Phosphorus-Peroxide Cage Cluster.” Inorg. Chem. 2016, 55(14), 7061-7067.

Dembowski, M.; Olds, T.A.; Pellegrini, K.L.; Hoffmann, C.; Wang, X.P.; Hickam, S.; He, J.H.; Oliver, A.G.; Burns, P.C. “Solution P-31 NMR Study of the Acid-Catalyzed Formation of a Highly Charged {U(24)Pp(12)} Nanocluster, [(UO2)(24)(O-2)(P2O7)(12)](48-), and Its Structural Characterization in the Solid State Using Single-Crystal Neutron Diffraction.” J. Am. Chem. Soc. 2016, 138(27), 8547-8553.

Miro, P.; Vlaisavljevich, B.; Gil, A.; Burns, P.C.; Nyman, M.; Bo, C. “Self-Assembly of Uranyl-Peroxide Nanocapsules in Basic Peroxidic Environments.” Chem. Eur. J. 2016, 22(25), 8571-8578.

Gao, Y.Y.; Szymanowski, J.E.S.; Sun, X.Y.; Burns, P.C.; Liu, T.B. “Thermal Responsive Ion Selectivity of Uranyl Peroxide Nanocages: An Inorganic Mimic of K+ Ion Channels.” Angew. Chem. Int. Ed. 2016, 55(24), 6887-6891.

Wylie, E.M.; Peruski, K.M.; Prizio, S.E.; Bridges, A.N.A.; Rudisill, T.S.; Hobbs, D.T.; Phillip, W.A.; Burns, P.C. “Processing used nuclear fuel with nanoscale control of uranium and ultrafiltration.” J. Nucl. Mater. 2016, 473, 125-130.

Soltis, J.A.; Wallace, C.M.; Penn, R.L.; Burns, P.C. “Cation-Dependent Hierarchical Assembly of U60 Nanoclusters into Macro-Ion Assemblies Imaged via Cryogenic Transmiision Election Microscopy.” J. Am. Chem. Soc. 2016, 138(1), 191-198.

Postdoctoral fellow, California Institute of Technology, 1994–96

PhD, Chemistry, University of Washington, 1994BS, Chemistry, Massachusetts Institute of Technology, 1988

Inorganic and Organic Reaction Mechanisms: Developing Catalysis for Energy and the Environment

Enhancing our understanding of the mechanisms of chemical reactions is critical to improve processes that interconvert between chemical and electrical energy or to make chemical products in a selective and environmentally benign way. The Brown group is addressing this general problem by making new inorganic or organometallic complexes with the aim of achieving reactivity through novel mechanisms.

Traditionally, oxidation-reduction reactions mediated by metal-containing compounds involve changes in both the oxidation state and bonding that directly involve those metal centers. We are exploring an alternative mode of redox reactivity, what we term “nonclassical” redox reactions, where bond-making or bond-breaking events occur at a metal center but oxidations or reductions occur not at the metal center but at redox-active ligands attached to the metal. These processes generate novel species with unusual electronic structure, which may be capable of unusual reactivity. Furthermore, separating the locus of electron transfer from that of changes in bonding mimics the heterogeneous catalysis involved in fuel cells, suggesting that nonclassical homogeneous reactions may lead to conceptual insights or practical advances in systems for interconverting electrical and chemical energy.

In some cases, we have observed reactions where both the oxidation state changes and the bonding changes take place at the ligand rather than the metal. This has allowed us to observe reactions at coordinatively saturated or even encapsulated metal centers that would normally be considered poor choices as catalysts because of the unavailability of open sites at the metal. We are currently engaged in elucidating the effect of the metal-ligand bonding on this ligand-centered reactivity and using that information to design new catalysts with enhanced reactivity, selectivity, or durability.

Awards

Fellow of the American Chemical Society, 2011University of Notre Dame Presidential Award, 2005NSF CAREER Award, 1998-2002Dupont Young Professor Award, 1998-2001Camille and Henry Dreyfus Foundation New Faculty Award,

1996


Marshall-Roth, T.; Brown, S.N. “Redox activity and π bonding in a tripodal seven-coordinate molybdenum(VI) tris(amidophenolate).” Dalton Trans. 2015, 44, 677-685.

Shekar, S.; Brown, S.N. “Mechanism and Selectivity of Methyl and Phenyl Migrations in Hypervalent Silylated Iminoquinones.” J. Org. Chem. 2014, 79, 12047-12055.

Ranis, L.G.; Werellapatha, K.; Pietrini, N.J.; Bunker, B.A.; Brown, S.N. “Metal and Ligand Effects on Bonding in Group 6 Complexes of Redox-Active Amidodiphenoxides.” Inorg. Chem. 2014, 53 (19), 10203-10216.

Shekar, S.; Brown, S.N. “Mixed amidophenolate-catecholates of molybdenum (VI).” Dalton Trans. 2014, 43 (9), 3601-3611.

Cipressi, J.; Brown, S.N. “Octahedral to trigonal prismatic distortion driven by subjacent orbital pi antibonding interactions and modulated by ligand redox noninnocence.” Chem. Commun. 2014, 50 (59), 7956-7959.

Randolph, A.H.; Seewald, N.J.; Rickert, K.; Brown, S.N. “Tris(3,5-di-tert-butylcatecholato)molybdenum(VI): Lewis Acidity and Nonclassical Oxygen Atom Transfer Reactions.” Inorg. Chem. 2013, 52 (21), 12587-12598.

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JON CAMDENAssociate Professor


IAN CARMICHAELProfessor Director, Radiation Laboratory(574) 631-4502 [email protected]


PhD, Physical and Theoretical Chemistry, University of Glasgow, Scotland, 1974BSc (1st Class Hons.), Chemistry, University of Glasgow,

Scotland, 1971

Quantum Chemistry of Reactive Intermediates Molecular Magnetic Properties Theoretical Radiation Chemistry

Ionizing radiation pervades our environment and affects all life on earth. The absorption of this impinging energy can produce profound chemical and biochemical transformations in the materials irradiated. Research at the Notre Dame Radiation Laboratory, the premier facility for radiation chemistry supported by the Division of Chemical Science, Geosciences and Biosciences, Basic Energy Sciences, Office of Science, United States Department of Energy, utilizes a unique constellation of experimental tools in a strong collaborative environment to build a fundamental molecular-level understanding of these interactions.

Knowledge gained from these studies provides the scientific basis for addressing challenges in, for example, capture and chemical conversion of solar energy, nuclear power generation, environmental waste management and remediation, and medical radiation therapies.

Opportunities for focused interdisciplinary investigations are evidenced by the presence of graduate students drawn from the departments of chemistry and biochemistry, physics, and chemical and biomolecular engineering, in addition to student visitors from other national and international universities.

Carmichael’s work is centered on the application of quantum chemistry to unravelling the course of electron-driven processes in the condensed phase, such as excited state and radical formation and identification in the radiolysis of liquids and solutions. Radiation effects in heterogeneous systems and at interfaces, such as those between water and ceramic oxides, are modeled. We also probe charge separation and transport in conjugated polymers, spin coupling in biomolecules, and radiation damage during macromolecular crystallography, a key roadblock in protein structure determination.

Publications

Bury, C.; McGeehan, J.E.; Antson, A.; Carmichael, I.; Gerstel, M.; Shevtsov, M.; Garman, E.F. “RNA protects a nucleoprotein complex against radiation damage.” Acta Crystallogr. 2016, D72, 648-657.

Hadad, M.J.; Zhang, W.; Turney, T.; Sernau, L.; Wang, X.; Woods, R.; Incandela, A.; Surjancev, I.; Wang, A.; Yoon, M-K.; Coscia, A.; Euell, C.; Meredith, R.; Carmichael, I.; Serianni, A.S. “NMR Spin-Couplings in Saccharides: Relationships Between Structure, Conformation, and the Magnitudes of JHH, JCH and JCC Values.”NMR in Glycoscience and Glycotechnology, K. Katos and T. Peters, Eds. 2016. Royal Society of Chemistry.

Bury, C.; Carmichael, I.; McGeehan, J.E.; Garman, E.F. “Radiation damage with nucleoprotein complexes studied by macromolecular X-ray crystallography.” Radiat. Phys. Chem. 2016 [DOI 10.1016/j.radphyschem.2016.05.023]

Bury, C.; Garman, E.F.; Ginn, H.M.; Ravelli, R.B.G.; Carmichael, I.; Kneale, G.; McGeehan, J.E. “Radiation damage to nucleoprotein complexes in macromolecular crystallography.” J. Synchotron Radiat. 2015, 22, 213-224.

Dawley, M.M.; Tanzer, K.; Carmichael, I.; Denifl, S.; Ptasinska, S. “Dissociative electron attachment to the gas-phase nucleobase hypoxanthine.” J. Chem. Phys. 2015, 142, 21501.

Postdoctoral Researcher, Northwestern University, 2005-2008PhD, Physical chemistry, Stanford University, 2005BS, Chemistry and Music, University of Notre Dame, 2000

Fundamental Optical Properties of Metallic Nanostructures

Research in the Camden group explores the fundamental optical properties of metallic nanostructures and applies this knowledge to develop new analytical methods. Our studies attempt to bridge the gap between physical and analytical chemistry. Areas of particular interest are: (1) ultrasensitive detection schemes for nuclear forensics and environmental pollutants, (2) the expansion of surface enhancement to nonlinear spectroscopies, and (3) using sub-nanometer plasmon imaging in the electron microscope to understand the response of plasmon-assisted catalysis. Throughout our work, we put a special emphasis on exploring systems that are amenable to high-level theoretical methods and making close connections with theoretical research groups.

Many applications of plasmonic nanoparticles, of which surface enhanced spectroscopy is just one, require an intimate understanding of the nanoparticle LSPR. Electron energy loss spectroscopy (EELS) in the scanning transmission electron microscope (STEM) has emerged as a technique capable of mapping the energy and spatial distribution of plasmon modes at the nanometer scale. Our group uses the powerful combination of STEM/EELS and optical scattering to probe the plasmon response of metallic structures at the sub-nanometer level. These studies focus on understanding the response of substrates for surface-enhanced spectroscopy and plasmon-assisted catalysis.

Two-photon transitions, for example, play an essential role in energy up-conversion, all-optical switching, optical data storage, 3D lithography, and biological imaging. While plasmonic nanostructures have been utilized extensively to enhance linear spectroscopies, such as surface enhanced Raman scattering (SERS), almost no effort has been devoted to studying the enhancement of nonlinear spectroscopies, despite their potential impact. The Camden group is currently studying a prototypical nonlinear spectroscopy: surface enhanced hyper-Raman scattering (SEHRS). We have recently demonstrated single molecule sensitivity with SEHRS and discovered the surprising importance of non-Condon effects in common dye molecules such as Rhodamine 6G by using SEHRS. The large enhancement factors of SERS classify it as a highly sensitive spectroscopy technique; thus, presenting SERS often

finds application in detection of chemical and biological analytes. The general applicability of SERS, however, is limited by the ability of the analyte molecule to bind specifically to the surface. Therefore, we are developing modified SERS substrates for a field-deployable detection scheme for the actinides and environmental pollutants such as hydrazine.

AwardsResearch and Creative Achievement Award, University of

Tennessee, 2013NSF CAREER Award, 2012NSF Graduate Research Fellowship, 2001


Wu, Y.Y.; Li, G.L.; Cherqui, C.; Bigelow, N.W.; Thakkar, N.; Masiello, D.J.; Camden, J.P.; Rack, P.D. “Electron Energy Loss Spectroscopy Study of the Full Plasmonic Spectrum of Self-Assembled Au-Ag Alloy Nanoparticles: Unraveling Size, Composition, and Substrate Effects.” ACS Photonics 2016, 3(1), 130-138.

Simmons, P.D.; Turley, H.K.; Silverstein, D.W.; Jensen, L.; Camden, J.P. “Surface-Enhanced Spectroscopy for Higher-Order Light Scattering: A Combined Experimental and Theoretical Study of Second Hyper-Raman Scattering.” J. Phys. Chem. Lett. 2015, 6(24), 5067-5071.

Gu, X.; Camden, J.P. “Surface-Enhanced Raman Spectroscopy-Based Approach for Ultrasensitive and Selective Detection of Hydrazine.” Anal. Chem. 2015, 87(13), 6460-6464.

Li, G.L.; Cherqui, C.; Wu. Y.Y.; Bigelow, N.W.; Simmons, P.D.; Rack, P.D.; Masiello, D.J.; Camden, J.P. “Examining Substrate-Induced Plasmon Mode Splitting and Localization in Truncated Silver Nanospheres with Electron Energy Loss Spectroscopy.” J. Phys. Chem. Lett. 2015, 6(13), 2569-2576.

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FRANCIS J. CASTELLINOKleiderer/Pezold Professor,

Director, W.M. Keck Center for Transgene Research


MAYLAND CHANGResearch Professor Director, Chemistry Biochemistry- Biology Interface (CBBI) Program(574) [email protected]


Postdoctoral Fellow, Columbia University, 1986-1988 PhD, Chemistry, University of Chicago, 1986 BS, Chemistry, University of Southern California, 1981 BS, Biological Sciences, University of Southern California,

1980

Biomedical Research, Drug Discovery and Development, Drug Metabolism and Pharmacokinetics

The Chang laboratory conducts biomedical research to understand the molecular basis of disease and to design small molecules for therapeutic intervention. Some of our current projects are described below.

Chronic wounds are a complication of diabetes that results in >70,000 lower-limb amputations in the United States every year. The reasons for why diabetic wounds are recalcitrant to healing are not fully understood, and there is a single FDA-approved drug to treat diabetic foot ulcers; however it is associated with increased mortality and cancer. We used an affinity resin that binds only the active forms of MMPs and related ADAMs coupled with quantitative proteomics to identify active MMP-8 and MMP-9 in diabetic wounds. Using the selective MMP-9 inhibitor ND-336 led to acceleration of wound healing by lowering inflammation, enhancing angiogenesis, and by re-epithelialization of the wound, thereby reversing the pathological condition. The detrimental role of MMP-9 was confirmed with diabetic MMP-9-knockout mice. Furthermore, the beneficial role of MMP-8 in wound healing was determined with a selective MMP-8 inhibitor and by topical application of the proteinase MMP-8. The combined topical application of ND-336 (a small molecule) and active recombinant MMP-8 (an enzyme) enhanced healing even more, in a strategy that holds considerable promise in healing of diabetic wounds. We are currently identifying and quantifying active MMPs in patients with diabetic foot ulcers.

Another project involves the design, syntheses, and evaluation of novel antibiotics to treat methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile infections. We have identified novel classes of antibacterials. The quinazolinones are active in vivo against MRSA and have an unprecedented mechanism of action, binding to the allosteric site of PBP2a and triggering conformational changes that result in opening of the active site of PBP2a. The oxadiazoles are bactericidal, exhibit efficacy comparable or better to that of linezolid in mouse peritonitis and neutropenic thigh models of infection, have excellent pharmacokinetic properties, synergize with

β-lactam antibiotics, and exhibit a long post-antibiotic effect. We are currently leading optimizing the oxadiazoles to impart in vivo C. difficile activity.

Awards

Pathway to Stop Diabetes Award, American Diabetes Association, 2015

Special Merit Award, The Dow Chemical Company, 1992Special Recognition Award, Pharmacia & Upjohn, Inc., 1998National Institutes of Health Postdoctoral Fellowship, 1987-

1988 Marc Galler Perry Prize, The University of Chicago, 1987


Janardhanan, J.; Meisel, J.E.; Ding, D.; Schroeder, V.A.; Wolter, W.R.; Mobashery, S.; Chang, M. “In Vitro and In Vivo Synergy of the Oxadiazole Class of Antibacterials with β-Lactams” Antimicrob. Agents Chemother. 2016, 60(9), 5581-5588.

Bouley, R.; Ding, D.; Peng, Z.; Bastian, M.; Lastochkin, E.; Song, W.; Suckow, M.A.; Schroeder, V.A.; Wolter, W.R.; Mobashery, S.; Chang, M. “Structure-Activity Relationship for the 4(3H)-Quinazolinone Antibacterials” J. Med. Chem. 2016, 59, 5011-5021.

Chang, M. “Restructuring of the Extracellular Matrix in Diabetic Wounds and Healing: A Perspective” Pharmacol. Res. 2016, 107, 243-248.

Lee, M; Chen, Z.; Tomlinson, B.N.; Gooyit, M.; Hesek, D.; Juarez, M.R.; Nizam, R.; Boggess, B.; Lastochkin, E.; Schroeder, V.A.; Wolter, W.R.; Suckow, M.A.; Cui, J.; Mobashery, S.; Gu, Z.; Chang, M. “Water-Soluble MMP-9 Inhibitor Reduces Lesion Volume after Severe Traumatic Brain Injury” ACS Chem. Neurosci. 2015, 6, 1658-1664.

Gao, M.; Nguyen, T.T.; Suckow, M.A.; Wolter, W.R.; Gooyit, M.; Mobashery, S.; Chang, M. “Acceleration of Diabetic Wound Healing Using a Novel Protease-Anti-Protease Combination Therapy” Proc. Nat. Acad. Sci. 2015, 112, 15226-15231.

Postdoctoral researcher, Duke University, 1968–70PhD, Biochemistry, University of Iowa, 1968MS, Biochemistry, University of Iowa, 1966BS, Chemistry, University of Scranton, 1964

Structural Biology and in vivo Mechanisms of Blood Coagulation and Fibrinolysis

Professor Castellino’s research involves the structure, function, and activation of proteins that participate in blood coagulation and blood-clot dissolution. The in vivo mechanisms of the roles of these proteins in these processes are being addressed through in vivo targeted gene-replacement approaches. Major tools being used include cloning, mutagenesis, and expression of variant recombinant proteins and individual protein domains, and immunochemical studies of the proteins, as well as physical and chemical analysis of their solution structures. Current work stresses the role of the fibrinolytic system in the virulence of Group A streptococcus, which infects ~ 700M/annually, worldwide. Some strains of these bacteria number can disseminate in the body, leading to serious conditions of necrotizing faciitis, several cases of which hav recentlye received worldwide attention.

Another project receiving attention emphasizes the structure- function relationships of small gamma-carboxyglutamic acid (Gla)-containing peptides from marine cone snails that target the brain NMDA receptor. These peptides inhibit the flow of calcium into neuronal cells, this latter event being responsible for the neuropathology associated with stroke, epilepsy, Alzheimer’s disease, ALS, etc. The biochemical, pharmacological, and neurobiological mechanisms of the actions of these peptides are being investigated.

To determine the biological functions of genes encoding coagulation and clot-dissolving proteins in hemostasis, cancer, inflammation and infection, wound healing, embryonic implantation and development, metastases, and atherosclerosis, gene deletion and other gene-targeting experiments are being performed in mice, in conjunction with phenotyping of these animals.

Awards

Editor-in-chief, Current Drug Targets, 2001-present Wyeth International Prize for contributions to firbrinolysis,

2008 Elected Fellow, American Heart Association, 2001Elected Fellow, American Association for the Advancement

of Science, 1988

National Institutes of Health Research Career Development Award, 1974–1979

Camille and Henry Dreyfus Teacher-Scholar Grant, 1974Elected fellow of the New York Academy of Sciences, 1977


Bao, Y.J.; Liang, Z.; Mayfield, J.A.; Donahue, D.L.; Carothers, K.E.; Lee, S.W.; Ploplis, V.A.; Castellino, F.J. “Genomic Characterization of a Pattern D Streptococcus pyogenes emm53 Isolate Reveals a Genetic Rationale for Invasive Skin Tropicity.” J. Bacteriol. 2016, 198(12), 1712-1724.

Mamczak, C.N.; Maloney, M.; Fritz, B.; Boyer, B.; Thomas, S.; Evancs, E.; Ploplis, V.A.; Castellino, F.J.; McCollester, J.; Walsh, M. “Thromboelastography in Orthopaedic Trauma Acute Pelvic Fracture Restoration: A Descriptive Pilot Study.” J. Orthop. Trauma 2016, 30(6), 299-305.

Agrahari, G.; Liang, Z.; Glinton, K.; Lee, S.W.; Ploplis, V.A.; Castellino, F.J. “Streptococcus pyogenes Employs Strain-dependent Mechanisms of C3b Inactivation to Inhibit Phagocytosis and Killing of Bacteria.” J. Biol. Chem.2016, 291(17), 9181-9189.

Cheriyan, J.; Balsara, R.D.; Hansen, K.B.; Castellino, F.J. “Pharmacology of triheteromeric N-Methyl-D-Aspartate Receptors.” Neurosci. Lett. 2016, 617, 240-246.

Motley, M.P.; Madsen, D.H.; Jurgensen, H.J.; Spencer, D.E.; Szabo, R.; Holmbeck, K.; Flick, M.J.; Lawrence, D.A. Castellino, F.J.; Weigert, R.; Bugge, T.H. “A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo.” Blood 2016, 127(9), 1085-1096.

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PATRICIA L. CLARKRev. John Cardinal O’Hara, C.S.C.,

Professor(574) 631-8353 [email protected]


National Institutes of Health postdoctoral fellow, Massachusetts Institute of Technology, 1997–2001

PhD, Molecular Biophysics, University of Texas Southwestern Medical Center, Dallas, 1997

BS, Chemistry, Georgia Institute of Technology, 1991

Protein Folding in the Cellular Environment

Understanding how proteins fold is of utmost importance for predicting protein structure from genomic sequence data, designing novel proteins, and understanding how and why protein folding mechanisms can fail. Failure of protein folding mechanisms, often due to genetic mutations or adverse conditions such as thermal or chemical stress, is the cause of numerous human diseases, including cystic fibrosis, Alzheimer’s disease, juvenile cataracts, and many forms of cancer.

Research led by Clark focuses on how the cellular environment affects protein folding mechanisms, particularly for complex protein structural topologies such as those that include β-sheet structure.

Of particular interest to Clark and her team is the role of the ribosome in protein folding. Ribosomes are the large (2-4 MDa) molecular machines that synthesize proteins, and the surface of the ribosome is therefore the first cellular surface encountered by every newly synthesized polypeptide chain. The group is investigating the interactions of nascent polypeptides with the surfaces of the ribosome in order to determine the effect of ribosomal interactions on polypeptide chain conformation and subsequent protein folding processes. The laboratory also develops bioinformatic algorithms to predict where ribosomes will pause during protein synthesis and designs model systems to test these predictions and measure the effects of translation pausing on protein folding mechanisms.

A related interest is how proteins fold after they are secreted across a membrane. Autotransporters are the largest class of secreted virulence proteins in Gram-negative bacterial pathogens, and they must cross two membranes before folding on the extracellular surface of the bacteria. Clark and her team are investigating how the different environments encountered by the autotransporter after secretion across each of these membranes alters the environment for protein folding and promotes efficient secretion.

Awards

Michael & Kate Barany Award for Young Investigators, Biophysical Society, 2013American Heart Association National Scientist Development

Award, 2003-2007NSF CAREER Award, 2003-2008NIH NRSA Postdoctoral Fellowship, 1998-2001NIH Biophysics Predoctoral Training Fellowship, 1994-1997


Jacobson G.N. & Clark P.L. (2016) Quality over quantity: Optimizing co-translational protein folding with non-‘optimal’ synonymous codons. Current Opinion in Structural Biology 38, 102-110.

Besingi R.N. & Clark P.L. (2015) Extracellular protease digestion to evaluate membrane protein cell surface localization. Nature Protocols 10, 2074-2080.

Chaney J.L. & Clark P.L. (2015) Roles for synonymous codon usage in protein biogenesis. Annual Review of Biophysics 44,143-166.

Drobnak I., Braselmann E. & Clark P.L. (2015) Multiple driving forces required for efficient secretion of autotransporter virulence proteins. Journal of Biological Chemistry 290, 10104-10116.

Sander I.M., Chaney J.L. & Clark P.L. (2014) Expanding Anfinsen’s principle: Contributions of synonymous codon selection to rational protein design. Journal of the American Chemical Society 136, 858-861.

STEVEN A. CORCELLIAssociate ProfessorAssociate Chair(574) 631-2631 [email protected]

Postdoctoral researcher, chemistry, University of Wisconsin, 2002–05

PhD, Chemistry, Yale University, 2002ScB, Chemistry, Brown University, 1997

Theoretical and Computational Studies of Biomolecular Structure and Dynamics

Dynamics of water at DNA interfaces: The objective of this project is to characterize water dynamics at DNA interfaces. While it is well established that hydration is essential to the stability and function of biomolecules, its role as an active player in important biological processes, such as allosteric regulation, folding, reaction mechanisms, and molecular recognition, is not fully understood. We are investigating the solvation response in DNA of Hoechst 33258, a minor-groove binder, and Coumarin 102 a guanine-cytosine base-pair analogue. Decompositions of the computed solvation response into contributions from water, DNA, and ions will greatly aid in the interpretation of time-dependent fluorescence measurements for these systems.

Infrared probes of biomolecular structure and dynamics: We are developing robust computational protocols for the simulation of infrared spectra of site-specific carbon-deuterium (C-D) and nitrile (C≡N) probes in biological contexts. The objective of these studies is to connect the information contained in the experimentally measured infrared absorption spectra to local conformational structure and flexibility. We are also ultimately interested in developing methods to calculate chemical-exchange two-dimensional infrared spectra to aid in the interpretation of novel experiments that employ C≡N labels as probes of hydrogen-bond dynamics. Such probes could be used to measure local hydration dynamics at biomolecular interfaces.

Awards

Fellow, American Chemical Society, 2016Director of Graduate Studies, University of Notre Dame,

2015Rev. Edmund P. Joyce, C.S.C. Award for Excellence in

Undergraduate Teaching, 2012Kavli Fellow, National Academies of Science and Alexander

von Humboldt Foundation, 2011Sloan Research Fellowship, 2009NSF CAREER Award, 2009Camille and Henry Dreyfus New Faculty Award, 2005Ruth L. Kirchstein National Research Service Award, 2003-

2005


Floisand, D.J; Corcelli, S.A. “Computational Study of Phosphate Vibrations as Reporters of DNA Hydration.” J. Phys. Chem. Lett. 2015, 6, 4012.

Adhikary, R.; Zimmermann, J.; Liu, J.; Forrest, R.P.; Janicki, T.D.; Dawson, P.E.; Corcelli, S.A.; Romesberg, F.E. “Evidence of an Unusual N-H---N Hydrogen Bond in Proteins.” J. Am. Chem. Soc. 2014, 136, 13474-13477.

Terranova, Z.L.; Corcelli, S.A. “Molecular Dynamics Investigation of the Vibrational Spectroscopy of Isolated Water in an Ionic Liquid.” J. Phys. Chem. B 2014, 118 (28), 8264-8272

Wasio, N.A.; Quardokus, R.C.; Forrest, R.P.; Lent, C.S.; Corcelli, S.A.; Christie, J.A.; Henderson, K.W.; Kandel, S.A. “Self-assembly of hydrogen-bonded two-dimensional quasicrystals.” Nature 2014, 507 (7490), 86.

Quardokus, R.C.; Wasio, N.A.; Christie, J.A.; Henderson, K.W.; Forrest, R.P.; Lent, C.S.; Corcelli, S.A.; Kandel, S.A. “Hydrogen-bonded clusters of ferrocenecarboxylic acid on Au (111).” Chem. Commun. 2014, 50 (71), 10229-10232.

Terranova, Z.L.; Corcelli, S.A. “On the Mechanism of Solvation Dynamics in Imidazolium-Based Ionic Liquids.” J. Phys. Chem. B 2013, 117 (49), 15659-15666.

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KAREN COWDEN DAHLAdjunct Assistant Professor



Postdoctoral fellow, University of New Mexico, 2004-2008PhD, Cell and Molecular Biology, University of

Pennsylvania, 2004BS, Cell and Molecular Biology, Texas Tech University, 1999

Biochemical and Molecular Mechanisms of Cancer Progression

Ovarian cancer is the fifth leading cause of cancer death of women in the United States. The vast majority of women (>70 percent in the United States) diagnosed with ovarian cancer have advanced disease at the time of diagnosis (the tumor has spread or metastasized). For these women, the survival rates are less than 25 percent. Importantly, ovarian cancer is >90 percent curable if detected early (prior to metastatic spread). Unfortunately at this point in time, we do not have a good understanding of ovarian cancer at the molecular level. The goal of the Dahl laboratory is to study the molecules that are important in promoting ovarian

cancer progression, specifically to determine how a tumor “learns” how to metastasize and acquire treatment resistance so that we can better prevent, diagnose, and treat ovarian cancer.

The laboratory has discovered that a transcriptional regulator, known as ARID3B, is elevated in ovarian cancer. We are investigating how ARID3B promotes tumor growth and chemoresistance. The goal of the laboratory is to biochemically and molecularly elucidate the functions of ARID3B, in order to better understand cancer progression. We utilize both in vivo and in vitro models to uncover the role of ARID3B in cancer cells.


Kurkewich, J.L.; Klopfenstein, N.; Hallas, W.M.; Wood, C.; Sattler, R.A.; Das, C.; Tucker, H.; Dahl, R.; Cowden Dahl, K.D. “ARID3B is Critical for B Lymphocyte Development.” PloS One 2016, 11(8), e0161468.

Bobbs, A.S.; Cole, J.M.; Cowden Dahl, K.D. “Emerging and Evolving Ovarian Cancer Animal Models.” Cancer Growth Metastasis 2015, 8, 29-36.

Bobbs, A.; Gellerman, K.; Hallas, W.M.; Joseph, S.; Yang, C.; Kurkewich, J.; Cowden Dahl, K.D. “ARID3B Directly Regulates Ovarian Cancer Promoting Genes.” PLoS One 2015, 10(6), e0131961.

Mitra, A.K.; Davis, D.A.; Tomar, S.; Roy, L.; Gurler, H.; Xie, J.; Lantvit, D.D.; Cardenas, H.; Fang, F.; Liu, Y.; Loughran, E.; Yang, J.; Stack, M.S.; Emerson, R.E.; Cowden Dahl, K.D.; Barbolina, M.V.; Nephew, K.P.; Matei, D.; Burdette, J.E. “In vivo tumor growth of high-grade serous ovarian cancer cell lines.” Gynecol. Oncol. 2015, 138(2), 372-377.

Roy, L.; Samyesudhas, S.J.; Carrasco, M.; Li, J.; Joseph, S.; Dahl, R.; Cowden Dahl, K.D. “ARID3B increases ovarian tumor burden and is associated with a cancer stem cell gene signature.” Oncotarget 2014, 5(18), 8355-8366.

Samyesudhas, S.J.; Roy, L.; Cowden Dahl, K.D. “Differential expression of ARID3B in normal adult tissue and carcinomas.” Gene 2014, 543(1), 174-180.

NORMAN J. DOVICHIGrace-Rupley Professor(574) [email protected]

Postdoctoral Fellow, Los Alamos Scientific Laboratory, 1980-1982

PhD, Physical-analytical Chemistry, University of Utah, 1980BS, Chemistry and Mathematic, northern Illinois University,

1976

Physical Chemistry

Norman Dovichi is a superb scholar with deep insights into the way in which chemical measurements can affect other fields, principally, but not solely, biomedicine. Dovichi is well known for having developed the measurement tools that allowed the human genome project to be completed. Indeed, he was named as an “unsung hero of the human genome project” by Science magazine in 2001. Dovichi has authored more than 235 publications, 8,500 citations, presented 35 named and special lectures, over 100 plenary lectures, and 320 invited lectures, as well as numerous prestigious awards. He is also associate editor of the journal, Analytical Chemistry.

Currently, the focus of Dovichi’s work is on chemical cytometry—the complete, accurate analysis of the biochemical machinery of a single living cell as a function of the state of the cell in the cell cycle and its relation to disease state. This draws him to develop new measurement science because of the extreme challenges posed by the dynamic range (proteins present in copy numbers that vary by > 1010), sensitivity (typically requiring single molecule capabilities), and recalcitrance of the measurement problem. This work pushes the envelope in terms of technical capabilities. Dovichi is focusing his efforts on those areas where ultrasensitive chemical measurements can aid in the intelligent management of a course of therapy.

Awards

Fellow, Royal Society of Chemistry, 2012Robert Boyle Award, Royal Society of Chemistry, 2012Ralph Adams Award, PittCon, 2007Inaugural member, National Institutes of Health College of

Reviewers 2010-2012Spectrochemical Analysis Award, Analytical Division,

American Chemical Society, 2003Unsung Hero of the Human Genome Project (Science 2001;

291: pg 1201)Heinrich Emanuel Merck Award for Analytical Chemistry, 2000Chemical Instrumentation Award, Analytical Division,

American Chemical Society, 1996The Steacie Prize, E.W.R. Steacie Memorial Fund, 1991J. Gordin Kaplan Award for Excellence in Research,

University of Alberta, 1997


Sun, L.L.; Dubiak, K.M.; Peuchen, E.H.; Zhang, Z.B.; Zhu, G.J.; Huber, P.W.; Dovichi, N.J. “Single Cell Proteomics Using Frog (Xenopus laevis) Blastomeres Isolated from Early Stage Embryos, Which Form a Geometric Progression in Protein Content.” Anal. Chem. 2016, 88(13), 6653-6657.

Peuchen, E.H.; Sun, L.L.; Dovichi, N.J. “Optimization and comparison of bottom-up proteomic sample preparation for early-stage Xenopus laevis embryos.” Anal. Bioanal. Chem. 2016, 408(17), 4743-4749.

Sun, L.L.; Champrion, M.M.; Huber, P.W.; Dovichi, N.J. “Proteomics of Xenopus development.” Mol. Hum. Reprod. 2016, 22(3), 193-199.

Zhu, G.J.; Sun, L.L.; Heidbrink-Thompson, J.; Kuntumalla, S.; Lin, H.Y.; Larkin, C.J.; Mcgivneyiv, J.B.; Dovichi, N.J. “Capillary zone electrophoresis tandem mass spectrometry detects low concentration host cell impurities in monoclonal antibodies.” Electrophoresis 2016, 37(4), 616-622.

Zhang, Z.B.; Sun, L.L.; Zhu, G.J.; Cox, O.F.; Huber, P.W.; Dovichi, N.J. “Nearly 1000 Protein Identifications from 50 ng of Xenopus laevis Zygote Homogenate Using Online Sample Preparation on a Strong Cation Exchange Monolith Based Microreactor Coupled with Capillary Zone Electrophoresis.” Anal. Chem. 2016, 88(1), 877-882.

Schmudlach, A.; Felton, J.; Cipolla, C.; Sun, L.L.; Kennedy, R.T.; Dovichi, N.J. “Sample preparation protocol for bottom-up proteomic analysis of the secretome of the islets of Langerhans.” Analyst 2016, 141(5), 1700-1706.

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Postdoctoral fellow, University of California Berkeley and Lawrence Berkeley National Laboratory, 2009–2011

PhD, Chemistry, Carnegie Mellon University, 2008MS, Polymer Chemistry, Fudan University, Shanghai, China,

2003BS, Polymer Chemistry, Fudan University, Shanghai, China,

2000

Organic Chemistry

Research in the Gao group focuses on synthesizing functional polymers with controlled nanostructures and understanding their fundamental structure-property relationships. These functional materials meet critical needs in the fields of biomedical materials, environmental remediation, and energy conservation. Initial targets include the development of advanced membranes for gas separation, solid conductive polymers for Li-ion batteries, multifunctional nanoparticles for biomedical diagnostics, and treatment of diseases.

A number of approaches, including modern organic synthesis, “living” polymerization techniques, and biomimetic programmed self assembly, are applied in our research. By building polymers ranging in size and complexity from oligomers, to multi-segmented block copolymers, and to shape-persistent hierarchical nanocomposites, various functionalities will be incorporated into these soft polymeric nanomaterials in a predetermined manner. The multidisciplinary nature in our research program allows students to acquire diverse synthetic and analytical skills and develop broad scientific vision in organic chemistry, polymer chemistry, and materials science. Several interesting research projects are:

1) Developing new methodologies for efficient polymer synthesis and functionalization

2) Biomimetic assembly of synthetic polymer chains into shape-persistent nanostructures

3) Exploiting nanostructured polymer materials for gas separation and selective absorption

4) Electro-active polymers and nanocomposites

Awards

NSF CAREER Award, 2016Army Young Investigator Program (YIP) Award, 2014UMass MRSEC Young Investigator Award, 2013AzkoNobel Award for Outstanding Graduate Research in

Polymer Chemistry, American Chemical Society, 2010Guy C. Berry Graduate Research Award, Carnegie Mellon

University, 2008McWilliams Fellowship, Carnegie Mellon University, 2007


Cao, X.; Shi, Y.; Wang, X.; Graff, R.W.; Gao, H. “Design a Highly Reactive Trifunctional Core Molecule to Obtain Hyperbranched Polymers with over a Million Molecular Weight in One-Pot Click Polymerization.”Macromolecules 2016, 49, 760-766.

Shi, Y.; Graff, R.W.; Cao, X.; Wang, X.; Gao, H. “Chain-Growth Click Polymerization of AB2 Monomers to Produce Hyperbranched Polymer with Low Polydispersity in One-Pot.” Angew. Chem. Int. Ed. 2015, 54, 7631-7635.

Wang, X.; Graff, R.W.; Shi, Y.; Gao, H. “One-pot Synthesis of Hyperstar Polymers via Sequential ATRP on Inimers and Functional Monomers in Aqueous Dispersed Media.” Polym. Chem. 2015, 6, 6739-6745.

Shi, Y.; Wang, X.F.; Graff, R.W.; Phillip, W.A.; Gao, H.F. “Synthesis of Degradable Molecular Brushes via a Combination of Ring-Opening Polymerization and Click Chemistry.” J. Polym. Sci. Pol. Chem. 2015, 53 (2), 239-248.

Lee. D; Zhang, C.Y., Gao, H.F. “Facile Production of Polypyrrole Nanofibers Using a Freeze-Drying Method.”Macromol. Chem. Physics 2014, 215 (7), 669-674.

Zhang, C.Y.; Wang, X.F.; Min, K.; Lee, D.; Wei, C.; Schulhauser, H.; Gao, H.F. “Developing Porous Honeycomb Films Using Miktoarm Star Copolymers and Exploring Their Application in Particle Separation.” Macromol. Rapid Comm. 2014, 35 (2), 221.227.

HAIFENG GAOAssistant Professor


J. DANIEL GEZELTERProfessorDirector of Undergraduate Studies(574) 631-7595 [email protected]

Postdoctoral researcher, Columbia University, 1996–99PhD, Chemistry, University of California at Berkeley, 1995BS, Chemistry and philosophy, Duke University, 1989

Theoretical and Computational Chemistry Molecular Dynamics of Condensed Phase Systems

Research in the Gezelter group involves theoretical and computational studies of the dynamics of complex, condensed-matter systems. The mechanism of heat and mass transport at complex interfaces is of particular interest. The group simulates metallic nanoparticles in liquid environments, lipid bilayers, the phase transitions of water, and glass-forming metals.

The major goal is to arrive at simple models that can explain the unexpected and emergent behavior of these systems. A second, but equally important goal is to develop and test novel theoretical methods that will advance computer simulation as a tool for research in the chemical sciences.

Because the systems studied are often complex many-body systems, it is necessary to utilize the analytical methods of statistical mechanics as well as state-of-the-art methods of computer simulation. A large component of the research in the group is the development of efficient algorithms to perform molecular dynamics simulations and to obtain useful information from them. We are particularly interested in O(N) methods for computing electrostatic interactions as well as non-equilibrium simulation methods.

Awards

NSF CAREER Award, 2002 Camille and Henry Dreyfus New Faculty Award, 1999National Science Foundation’s Faculty Early Career

Development AwardChurchill Scholar, University of Cambridge 1989-1990


Joseph R. Michalka, Andrew P. Latham, and J. Daniel Gezelter, “CO-induced restructuring on stepped Pt surfaces: A molecular dynamics study” J. Phys. Chem. C 120 (32), pp. 18180-18190, (2016).

Madan Lamichhane, Thomas Parsons, Kathie Newman, and J. Daniel Gezelter, “Real Space Electrostatics for multipoles. III. Dielectric properties,” J. Chem. Phys. 145, 074108 (2016).

Kelsey M. Stocker, Suzanne M. Neidhart and J. Daniel Gezelter, “Interfacial Thermal Conductance of Thiolate-Protected Gold Nanospheres,” J. Appl. Phys. 119 (2), 025106, (2016).

Joseph R. Michalka, and J. Daniel Gezelter, “Island Formation on Pt/Pd(557) Surface Alloys in the Presence of Adsorbed CO: A Molecular Dynamics Study,” J. Phys. Chem. C, 119 (25), pp 14239–14247 (2015).

Daniel C. Hannah, J. Daniel Gezelter, Richard D. Schaller, and George C. Schatz, “Reverse Non-Equilibrium Molecular Dynamics Demonstrates that Surface Passivation Controls Thermal Transport at Semiconductor-Solvent Interfaces,”ACS Nano 9 (6), pp 6278–6287 (2015).

J. Daniel Gezelter, “Open Source and Open Data Should be Standard Practices,” J. Phys. Chem. Lett. 6 (7), pp. 1168-1169 (2015).

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HOLLY V. GOODSONProfessor


Helen Hay Whitney Fellow, Geneva, Switzerland, 1995–2000

PhD, Biochemistry, Stanford University, 1995AB, Molecular Biology, Princeton University, 1988

Cytoskeletal Dynamics, Evolutionary Cell Biology

Goodson uses multifaceted approaches—biochemistry, molecular biology, bioinformatics, and computational biology—to address cell biological questions. She and her group focus on the microtubule cytoskeleton—the dynamic network of protein fibers that pulls the chromosomes apart at mitosis, acts as “railroad tracks” for intracellular transport, and organizes the cytoplasm. How does this network form? What governs its dynamic turnover? How do other parts of the cell (organelles, chromosomes, other parts of the cytoskeleton) interact with microtubules?

The answers to all of these questions lie in the biochemistry of tubulin and the proteins that interact with it. Explaining the behavior and function of the microtubule cytoskeleton on the basis of this biochemistry is the long-term goal of the Goodson group.

One focus is microtubule plus-end tracking proteins (+TIPs), a group of unrelated proteins that share the remarkable ability to “surf” on growing microtubule ends. +TIPs are master regulators of microtubule dynamics and also control interactions between microtubules and many other subcellular structures. Why do +TIPs dynamically track growing microtubule ends, and how do they do it? What is the functional significance of this behavior? Major foci at present include understanding why many +TIPs bind to other +TIPs, and how +TIPs help the microtubule cytoskeleton interface with the rest of the cell, including the actin cytoskeleton. These problems are basic questions of cell biology but also have deep relevance to fields such as developmental biology, neurobiology (including neurodegeneration), and cancer. The Goodson laboratory approaches these problems through a combination of classic biochemistry, modern cell biology, biophysics, and computational modeling. Additional related laboratory projects focus on other aspects of the cytoskeleton, including a microtubule-binding protein called Tau that is involved in Alzheimer’s disease.

A second long-term interest in the Goodson group is using molecular evolution to address cell biological questions. Goodson and her team analyze the set of related sequences present in the genome databases (nature’s mutagenesis experiments) with bioinformatic techniques such as phylogenetic analysis, homology

modeling, and conservation mapping. They use this information to make predictions about protein function and investigate structure/ function relationships. Although much of their work is done with existing software, they also collaborate with computer scientists in software development.


Alberico, E.O.; Zhu, Z.Q.C.; Wu, Y.F.O.; Gardner, M.K.; Kovar, D.R.; Goodson, H.V. “Interactions between the Microtubule Binding Protein EB1 and F-Actin.” J. Mol. Biol. 2016, 428(6), 1304-1314.

Weaver, A.A.; Halweg, S.; Joyce, M.; Lieberman, M.; Goodson, H.V. “Incorporating yeast biosensors into paper-based analytical tools for pharmaceutical analysis.” Anal. Bioanal. Chem. 2015, 407(2), 615-619.

Lynch, M.; Field, M.C.; Goodson, H.V.; Malik, H.S.; Pereira-Leal, J.B.; Roos, D.S.; Turkewitz, A.P.; Sazer, S. “Evolutionary cell biology: Two origins, one objective.” P. Natl. Acad. Sci. USA 2014, 111(48), 16990-16994.

Gupta, K.K.; Alberico, E.O.; Nathke, I.S.; Goodson, H.V. “Promoting microtubule assembly: A hypothesis for the functional significance of the plus TIP network.” Bioessays 2014, 36 (9), 818-826.

Li, C.L.; Li, J.; Goodson, H.V.; Alber, M.S. “Microtubule dynamic instability: the role of cracks between protofilaments.” Soft Matter 2014, 10(12), 2069-2080.

Gupta, K.K.; Li, C.; Duan, A.R.; Alber, M.S.; Goodson, H.V. “Mechanism for the catastrophe-promoting activity of the microtubule destabilizer Op18/stathmin.”’ P. Natl. Acad. Sci. USA 2013, 110(51), 20449-20454.

GREGORY V. HARTLANDProfessor(574) [email protected]

Postdoctoral Researcher, University of Pennsylvania, 1991–1994

PhD, Chemistry, University of California, Los Angeles, 1991BSc (Honors), Chemistry, University of Melbourne, Australia,

1985

Spectroscopy and Dynamics of Single Nanostructures

Research in the Hartland group focuses on understanding how metal and semiconductor nanomaterials interact with light and how they dissipate energy. We are particularly interested in studying single nanostructures by transient absorption microscopy, a technique that provides simultaneous high spatial and time resolution. The results from these measurements are used to improve the performance of nanostructured solar cells and to develop ultrasensitive nano-optical mechanical devices for detection of single bio-molecules. This work is very interdisciplinary and bridges the fields of physical and analytical chemistry, materials science, and optics.

Awards

Fellow of the Royal Society of Chemistry, 2014 ACS Fellow, 2011Fellow of the American Association for the Advancement of

Science, 2009Senior editor of The Journal of Physical ChemistryMember of the Editorial Advisory Board of Physical

Chemistry Chemical Physics


Johns, P.; Devadas, M.S.; Yu, K.; Hartland, G.V. “Role of Resonances in the Transmission of Surface Plasmon Polaritons between Nanostructures.” ACS Nano 2016, 10(3), 3375-3381.

Li, Z.; Mao, W.; Devadas, M.S.; Hartland, G.V. “Absorption Spectroscopy of Single Optically Trapped Gold Nanorods.” Nano Lett. 2015, 15, 7731-7735.

Yu,K.; Major, T.A.; Chakraborty, D.; Devadas, M.S.; Sader, J.E.; Hartland, G.V. “Compressible Viscoelastic Liquid Effects Generated by the Breathing Modes of Isolated Metal Nanowires.” Nano Lett. 2015, 15, 3964-3970.

Devadas, M.S.; Devkota, T.; Guha, S.; Shaw, S.K.; Smith, B.D.; Hartland, G.V. “Spatial Modulation Spectroscopy for Imaging and Quantitative Analysis of Single Dye-Doped Organic Nanoparticles Inside Cells.” Nanoscale 2015, 7, 9779-9785.

Devadas, M.S.; Devkota, T.; Johns, P.; Li, Z.; Lo, S.S.; Yu, K.; Huang, L.; Hartland, G.V. “Imaging Nano-Objects by Linear and Nonlinear Optical Absorption Microscopies.” Nanotechnology 2015, 26, 354001.

Johns, P.; Yu, K.; Devadas, M.S.; Li, Z.M.; Major, T.A.; Hartland, G.V. “Effect of substrate discontinuities on the propagating surface plasmon polariton modes in gold nanobars.” Nanoscale 2014, 6 (23), 14289-14296.

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PAUL HELQUISTProfessor

Associate Chair(574) 631-7822

[email protected]

Postdoctoral fellow, Harvard University, 1972–74PhD, Organic chemistry, Cornell University, 1972BA, Chemistry, University of Minnesota, 1969

Synthetic Methods: Transition Metal Organometallic

Reagents and Catalysts, Enantioselective Synthesis

Design and Synthesis of Therapeutic Agents for Rare Diseases and Cancer

Helquist’s research group is concerned with two broad areas: (1) the development of new methods in synthetic organic chemistry, including the preparation, structural study, and applications of new transition metal organometallic complexes as catalysts and reagents for asymmetric synthesis; and (2) the structure, synthesis, mechanism of action, and pharmaceutical development of biologically active compounds, including treatments for rare diseases and anti-tumor agents, many of which have their origins as natural products.

Helquist’s group has developed numerous synthetic methods employing iron, nickel, copper, rhodium, palladium, titanium, zirconium, magnesium, lithium, zinc, and samarium compounds as reagents or catalysts. They have employed many of these methods in the synthesis of complex natural products. Coupled with this organometallic work is the rational design of chiral transition metal catalysts through use of molecular mechanics computational techniques.

In the area of total synthesis, their laboratory studies compounds that show promise of being developed into clinically useful therapeutic agents. For several of the compounds that they study, the full structures have not been determined previously, and they therefore begin their work by employing high-field NMR and molecular mechanics computational techniques to determine the full, three- dimensional structures of these compounds. In the course of then pursuing total syntheses of these compounds, they often develop new methods. With synthetic materials in hand, they study structure-activity relationships and mechanisms of action. Helquist’s group employs this knowledge to obtain modified forms of the natural products to improve therapeutic properties, leading to the development of new pharmaceutical products. A special emphasis is currently being placed on treatments for rare, inherited

diseases for which no therapies have previously been available.

Other Activities

Consultant, pharmaceutical industryLecturer, American Chemical Society Short Courses and the

American Chemical Society Speakers Service Programs Collaborative research with laboratories in Sweden,

Denmark, and Japan

Awards

Tage Erlander Guest Professor of the Swedish National Research Council, University of Gothenburg and University of Stockholm, 2011-2012

Faculty Award, University of Notre Dame, 2010Joyce Award for Excellence in Undergraduate Teaching, 2009Kaneb Teaching Award, 2005, 2002


Lee, J.M.; Zhang, X.; Norrby, P.O.; Helquist, P.; Wiest, O. “Stereoselectivity in (Acyloxy)borane-Catalyzed Mukaiyama Aldol Reactions.” J. Org. Chem. 2016, 81, 5314-5321.

Wiest, O.; Maxfield, F.R.; Helquist, P. “Histone Deacetylase Inhibitors as Therapeitic Agents for Niemann-Pick Type C Disease.” U.S. Patent 9,333,222 May 10, 2016.

Byrd, K.M.; Arieno, M.D.; Kennelly, M.; Estiu, G.; Wiest, O.; Helquist, P. “Design and Synthesis of a Crosslinker for Studying Intracellular Steroid Trafficking Pathways.” Bioorg. Med. Chem. 2015, 23, 3843-3851.

Grigalunas, M.; Ankner, T.; Norrby, P.O.; Wiest, O.; Helquist, P. “Ni-Catalyzed Alkenylation of Ketone Enolates under Mild Conditions: Catalyst Identification and Optimization.” J. Am. Chem. Soc. 2015, 137, 7019-7022.

Grigalunas, M.; Norrby, P.O.; Wiest, O.; Helquist, P. “Sequential Single-Flask Multicomponent Pd-Catalyzed α,γ-Coupling of Ketone Enolates: Facile Preparation of Complex Carbon Scaffolds.” Angew. Chem. Int. Ed. 2015, 54, 11822-11825.

Grigalunas, M.; Ankner, T.; Norrby, P.O.; Wiest, O.; Helquist, P. “Palladium-Catalyzed Alkenylation of Ketone Enolates under Mild Conditions.” Org. Lett. 2014, 16 (15), 3970-3973.

PAUL W. HUBERProfessor(574) 631-6042 [email protected]

Visiting fellow, Yale University, 1997National Institutes of Health postdoctoral fellow,

University of Chicago, 1979–81PhD, Biochemistry, Purdue University, 1978BS, Biology and Chemistry, Boston College, 1973

RNA Expression, Processing, and Localization during Xenopus Development

Several important events transpire in Xenopus oocytes that determine proper development during embryogenesis. Because there is no transcription during the rapid cell division cycles of early embryogenesis, the oocyte must stockpile large amounts of ribosomes to support the demands of protein synthesis during the period following fertilization. There are two types of genes that encode 5S ribosomal RNA. One, the somatic-type, is transcribed at all stages of development, while the other, the oocyte-type, is only transcribed during oogenesis. Thus, the differential expression of these genes provides a good model system for studying the developmental control of transcription. The principal regulator of 5S rRNA gene transcription is TFIIIA. Huber’s group has found that this transcription factor becomes phosphorylated and SUMOylated at key times during development. These modifications apparently change the expression pattern of the 5S rRNA genes. The goal of this work is to understand these events at the molecular level.

The body plan of the frog begins to be determined in the unfertilized oocyte. The localization of some crucial mRNAs to specific regions of this single cell is a major mechanism that underlies proper development during embryogenesis. One mRNA, Vg1, encodes a member of the TGF-β family and is localized to the vegetal cortex of the mature oocyte. They have identified several proteins that bind to the region of Vg1 mRNA that determines its localization and translational control. Currently, their aim is to determine the role of each factor in localization, how these proteins interact and work together in this process, and to identify other components of the mRNA localization pathway.


Sun, L.; Dubiak, K.M.; Peuchen, E.H.; Zhang, Z.; Zhu, G.; Huber, P.W.; Dovichi, N.J. “Single Cell Proteomics Using Frog (Xenopus laevis) Blastomeres Isolated from Early Stage Embryos, Which Form a Geometric Progression in Protein Content.” Anal. Chem. 2016, 88, 6653-6657.

Zhang, Z.; Sun, L.; Zho, G.; Cox, O.F.; Huber, P.W.; Dovichi, N.J. “Nearly 1000 Protein Identifications from 50 ng of Xenopus laevis Zygote Homogenate Using Online Sample Preparation on a Strong Cation Exchange Monolith Based Microreactor Coupled with Capillary Zone Electrophoresis.” Anal. Chem. 2016, 88, 877-882.

Sun, L.; Champion, M.M.; Huber, P.W.; Dovichi, N.J. “Proteomics of Xenopus Development.” Mol. Hum. Reprod.2016, 22, 193-199.

Lambert, L.J.; Miller, M.J.; Huber, P.W. “Tetrahydrofuranyl and Tetrahydropyranyl Protection of Amino Acid Side-Chains Enables Synthesis of a Hydroxamate-Containing Aminoacylated tRNA” Org. Biomol. Chem. 2015, 13, 2341-2349.

Malik, M.Q.; Bertke, M.M.; Huber, P.W. “Small Ubiquitin-like Modifier (SUMO)-Mediated Repression of the Xenopus Oocyte 5S rRNA Genes” J. Biol. Chem.2014, 289, 35468-35481.

Sun, L.; Bertke, M.M.; Champion, M.M.; Zhu, G.; Huber, P.W.; Dovichi, N.J. “Quantitative Proteomics of Xenopus laevis Embryos: Expression kinetics of nearly 4000 proteins during early development” Sci. Reports 2014, 4, 4365.

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AMANDA HUMMONHuisking Foundation, Inc.

Associate Professor (574) 631-0583

[email protected]

Sallie Rosen Kaplan Postdoctoral Fellow, National Cancer Institute, NIH, 2005–2009 PhD, Analytical Chemistry, University of Illinois at Urbana-Champaign, 2004 AB, Chemistry, Cornell University, 1999

Proteomics of Cancer Cells

Cancer arises from insults to the genome. With genomic damage, the expression levels of genes are altered from their normal state. Changes in the genome, transcriptome, and proteome are highly conserved among samples from adenomas to carcinomas to metastases. Because genetic changes are commonly repeated among cancer patients, a better understanding of which genes, transcripts, and proteins are affected could have broad health implications. Therefore, the best ways to understand the molecular underpinnings of cancer are to dissect the deregulated pathways that are contributing to the cancer phenotype, identify the aberrantly expressed genes and their products, and decipher their effect on downstream targets. The Hummon research group develops high-throughput methods to evaluate both the transcriptome and the proteome in colorectal cancer cells.

Individual genes are perturbed, either with RNAi- based approaches or small molecule inhibitors, and then mRNA and protein profiles are generated. To profile the colorectal cancer transcriptome and proteome, we apply gene expression microarray and quantitative stable isotope labeling by amino acids in cell culture (SILAC) mass spectrometry protocols in colorectal cancer cell lines. Measurement and determination of the mRNA and protein profiles expose pivotal imbalances and downstream gene targets in colorectal cancer, revealing windows for potential therapeutic manipulation.

Awards

American Chemical Society Rising Star Award, 2016Joyce Award for Excellence in Undergraduate Teaching, 2016NSF Early CAREER Award, 2014Young Investigator Award, Spectroscopy Society of

Pittsburgh, 2011

WCIR Brigid G. Leventhal Scholar In Cancer Research Award, 2007

Sallie Rosen Kaplan Postdoctoral Fellowship, National Cancer Institute, 2005-2009


LaBonia, G.J.; Lockwood, S.Y.; Heller, A.; Spence, D.M.; Hummon, A.B. “Drug penetration and metabolism in 3-dimensional cell cultures treated in a 3D printed fluidic device: Assessment of irinotecan via MALDI imaging mass spectrometry.” Proteomics 2016, 16(11-12), 1814-1821.

Ludwig, K.R.; Dahl, R.; Hummon, A.B. “Evaluation of the mirn23a Cluster through an iTRAQ-based Quantitative Proteomic Approach.” J. Proteome Res.2016, 15(5), 1497-1505.

Ludwig, K.R.; Sun, L.; Zhu, G.; Dovichi, N.J.; Hummon, A.B. “Over 2,300 phosphorylated peptide identifications with single-shot capillary zone electrophoresis-tandem mass spectrometry in a 100 min separation.” Anal. Chem. 2015, 87(19), 9532-9537.

Yue, X.; Schunter, A.J.; Hummon, A.B. “Comparing Multi-Step IMAC and Multi-Step TiO2 Methods for Phosphopeptide Enrichment.” Anal. Chem. 2015, 87(17), 8837-8844.

Liu, X.; Hummon, A.B. “Mass Spectrometry Imaging of Drugs and Metabolites from Animal Models to Three-Dimensional Cell Cultures.” Anal. Chem. 2015, 87(19), 9508-9519.

Weaver, E.M.; Hummon, A.B. Keithley, R.B. “Chemometric analysis of MALDI mass spectrometric images of three-dimensional cell culture systems.” Anal. Methods 2015, 7, 7208-7219.

VLAD M. ILUC Assistant Professor (574) [email protected]

Postdoctoral fellow, California Institute of Technology, 2008–2011

PhD, Chemistry, University of Chicago, 2009MS, Chemistry, University of Chicago, 2003BS, Chemical Engineering, University Politehnica of

Bucharest, 2000

Inorganic Chemistry

The Iluc research group focuses on the activation of inert molecules, with an emphasis on the functionalization of C–H bonds in a catalytic manner. These are imperative scientific problems since less expensive and more readily available feedstocks than those currently used could be employed to meet some of the energy demands of our society. In a broad sense, the group is interested in green chemistry both in its approach (catalysis) and emphasis on using inert substrates (activation of CH bonds). The focus is on organometallic chemistry and especially on design of metal complexes that take advantage of latent reactivity. Two major areas are targeted: (1) the synthesis of electrophilic metal centers protected by weak interactions with a supporting ligand and (2) the characterization of systems using metal-ligand cooperation. In the first area, goals include alkane dehydrogenation, C–C coupling of olefins with ketones and nitriles, the development of E–H (E = O, S, N, P) functionalization reactions, such as anti-Markovnikov olefin hydration, hydrothiolation, hydroamination, and hydrophosphorylation. The second project will be applied to water activation and oxygen formation without photolytic activation.

The group will span synthesis, characterization, and mechanistic studies with an emphasis on understanding reactivity and design of new catalytic cycles. Students who are part of the group will become versatile scientists with skills drawing both on the synthesis of air-sensitive and air-stable metal complexes and on their characterization. Characterization methods include multinuclear NMR spectroscopy and X-ray crystallography on a routine basis with other types of spectroscopy (UV-vis-NIR, IR, EPR, Mossbauer, X-ray absorption) and characterization techniques (magnetism, cyclic voltammetry) employed in order to understand the properties of the newly synthesized metal complexes in detail. Reactivity behavior will be informed both by kinetics analysis and DFT calculations. All these results will be used in designing systems with better catalytic performance than those existing at the present.

Awards

NSF CAREER Award, 2016BP Postdoctoral Fellowship, 2008-2011McCormick Graduate Fellowship, 2002-2004


Vilanova, S.P.; Iluc, V.M. “Aryl and Benzyl C-H Activation of N-Substituted PNP Ligands.” Organometallics 2016, 35(12), 2110-2123.

Comanescu, C.C.; Iluc, V.M. “E-H (E=B, Si, Ge) bond activation of pinacolborane, silanes, and germanes by nucleophilic palladium carbene complexes.” Chem. Commun. 2016, 52(58), 9048-9051.

Cui, P.; Hoffbauer, M.R.; Vyushkova, M.; Iluc, V.M. “Heterobimetallic Pd-K carbene complexes via one-electron reductions of palladium radical carbenes.” Chem. Sci. 2016, 7(7), 4444-4452.

Cui, P.; Babbini, D.C.; Iluc, V.M. “C-H activation of ethers by pyridine tethered PCsp3P-type iridium complexes.”Dalton T. 2016, 45(24), 10007-10016.

Comanescu, C.C.; Iluc, V.M. “C-H Activation Reactions of a Nuclephilic Palladium Carbene.” Organometallics 2015, 34(19), 4684-4692.

Babbini, D.C.; Iluc, V.M. “Iridium PCsp3P-type Complexes with a Hemilabile Anisole Tether.” Organometallics 2015, 34(13), 3141-3151.

We have developed an imaging mass spectrometry method to examine the distribution of proteins in three-dimensional cell cultures. 3D cell cultures are commonly used tumor in vitro model systems. The figure shows the spatial distribution of analytes in a single HCT 116 spheroid. Ion intensity maps and mass spectra are displayed for four species. While m/z 12828 is located predominately in the central necrotic core of the 3D cell culture, the distribution of other species is more widespread throughout the structure.

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PRASHANT V. KAMATRev. John A. Zahm

Professor of Science(574) 631-5411 [email protected]

Postdoctoral researcher, University of Texas at Austin, 1981–83

Postdoctoral researcher, Boston University, 1979–81PhD, Physical Chemistry, Bombay University, 1979MS, Physical Chemistry, Bombay University, 1974

Nanostructured Assemblies Light Energy Conversion

In recent years, nanomaterials have emerged as the new building blocks to construct light-energy harvesting assemblies. Organic and inorganic hybrid structures provide new ways to improve se-lectivity and efficiency of catalytic processes. The key to creation of such nanohybrid assemblies is to understand their chemistry ata fundamental level. Kamat research group is actively engaged in building bridges between physical chemistry and material science to develop advanced nanomaterials that promise cleaner and more efficient light energy conversion.

The research efforts are mainly focused in three areas: (1) Pho-toinduced catalytic processes using semiconductor and metal nanoparticles, nanostructures and nanocomposites, (2) Develop-ment of light energy harvesting assemblies (e.g., quantum dots and inorganic-organic hybrid assemblies, metal halide perovskites) for next generation photovoltaics, (3) Metal nanoparticles and thio-lated metal clusters for energy conversion. The overall emphasis is to elucidate the chemical interactions— the rates and yields of interfacial charge transfer and charge recombination process-es—and improve charge separation efficiencies in light harvesting assemblies.

Awards

Irving Langmuir Award in Chemical Physics, American Chemical Society, 2013

Chemical Research Society of India Medal, 2011Fellow, American Chemical Society, 2011Fellow, American Association for the Advancement of

Science, 2010Fellow, The Electrochemical Society, 2008


Hoffman, J.B.; Schleper, A.L.; Kamat, P.V. “Transformation of Sintered CsPbBr3 Nanocrystals to Cubic CsPbI3and Gradient CsPbBrxI3-x through Halide Exchange. “J. Am. Chem. Soc. 2016, 138(27), 8603-8611.

Zaiats, G.; Kinge, S.; Kamat, P.V. “Origin of Dual Photoluminescence States in ZnS-CuInS2 Alloy Nanostructures.” J. Phys. Chem. C 2016, 120(19), 10641-10646.

Jara, D.H.; Stamplecoskie, K.G.; Kamat, P.V. “Two Distinct Transitions in CuxInS2 Quantum Dots. Bandgap versus Sub-Bandgap Excitations in Copper-Deficient Structures.” J. Phys. Chem. Lett. 2016, 7(8), 1452-1459.

Yoon, S.J.; Stamplecoskie, K.G.; Kamat, P.V. “How Lead Halide Complex Chemistry Dictates the Composition of Mixed Halide Perovskites.” J. Phys. Chem. Lett. 2016, 7(7), 1368-1373.

Alam, R.; Labine, M.; Karwacki, C.J.; Kamat, P.V. “Modulation of Cu2-xS Nanocrystal Plasmon Resonance through Reversible Photoinduced Electron Transfer.” ACS Nano 2016, 10(2), 2880-2886.

Manser, J.S.; Saidaminov, M.I.; Christians, J.A.; Bakr, O.M.; Kamat, P.V. “Making and Breaking of Lead Halide Perovskites.” Accounts Chem. Res. 2016, 49(2), 330-338.

S. ALEX KANDELAssociate Professor(574) 631-7837 [email protected]

Postdoctoral Fellow, Pennsylvania State University, 1999–2001

PhD, Physical Chemistry, Stanford University, 1999BS, Chemistry, Yale University, 1993

Surface Chemistry at the Molecular Scale

The Kandel research group studies how the physical, chemical, and electronic properties of surfaces are determined by the local chemical environment. “Local,” in our research, is defined by the natural length scales of individual atoms and molecules: Angstroms or nanometers. Understanding chemistry at the molecular scale is of fundamental interest, and it has significant practical importance: except for idealized cases and the most carefully controlled circumstances, real surfaces are tremendously heterogeneous, and this heterogeneity determines surface chemistry. We know this from everyday observations—for example, when we see the mottled rust cover and uneven pitting of an exposed piece of iron—and it underlies practical approaches to catalyst design and materials processing.

Our goal is to characterize and understand how the properties of each atom and molecule on a surface depend on neighboring atoms and molecules. We use scanning tunneling microscopy (STM) to image surfaces at the atomic scale; with this technique, we can measure a molecule’s properties and simultaneously determine its chemical environment, allowing for a true correlation of these properties to local surface structure.

Awards

CAREER Award, National Science Foundation, 2003Union Carbide Student Innovation Recognition Program,

2000American Chemical Society Novel Laureate Signature Award

in Graduate Education, 2000


Wasio, N.A.; Quardokus, R.C.; Brown, R.D.; Forrest, R.P.; Lent, C.S.; Corcelli, S.A.; Christie, J.A.; Henderson, K.W.; Kandel, S.A. “Cyclic Hydrogen Bonding in Indole Carboxylic Acid Clusters.” J. Phys. Chem. C 2015, 119(36), 21011-21017.

Christie, J.A.; Forrest, R.P.; Corcelli, S.A.; Wasio, N.A.; Quardokus, R.C.; Brown, R.; Kandel, S.A.; Lu, Y.H.; Lent, C.S.; Henderson, K.W. “Synthesis of a Neutral Mixed-Valence Diferrocenyl Carborane for Molecular Quantum-

Dot Cellular Automata Applications.” Angew. Chem. Int. Ed. 2015, 54(51), 15448-15451.

Quardokus, R.C.; Wasio, N.A.; Brown, R.D.; Christie, J.A.; Henderson, K.W.; Forrest, R.P.; Lent, C.S.; Corcelli, S.A.; Kandel, S.A. “Hydrogen-bonded clusters of 1,1’-ferrocenedicarboxylic acid on Au(111) are initially formed in solution.” J. Chem. Phys. 2015, 142(10), 101927.

Quardokus, R.C.; Wasio, N.A.; Christie, J.A.; Henderson, K.W.; Forrest, R.P.; Lent, C.S.; Corcelli, S.A.; Kandel, S.A. “Hydrogen-bonded clusters of ferrocenecarboxylic acid on Au(111).” Chem. Commun. 2014, 50 (71) 10229-10232.

Wasio, N.A.; Quardokus, R.C.; Forrest, R.P.; Lent, C.S.; Corcelli, S.A.; Christie, J.A.; Henderson, K.W.; Kandel, S.A. “Self-assembly of hydrogen-bonded two-dimensional quasicrystals.” Nature 2014, 507 (7490), 86.

Gans, A.R.; Jobbins, M.M.; Lee, D.Y.; Kandel, S.A. “Vacuum compatibility of silver and titanium parts made using three-dimensional printing.” J. Vac. Sci. Technol. A 2014, 32 (2), 023201.

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NRC Postdoctoral researcher, JILA/NIST/University of Colorado, 1998–2001

PhD, Physical Chemistry, Massachusetts Institute of Technology, 1993–1998

BA, Chemistry, Washington University at St. Louis, 1993

Low-Dimensional Nanomaterials

Both nanoscience and nanotechnology focus on understanding and putting to use materials with nanometer-sized dimensions. On such length scales (between those of bulk materials and molecular compounds) interesting and unusual changes occur to the optical and electrical properties of semiconductors, semi-metals, and metals. Such size dependent optical and electrical phenomena offer a wealth of exciting possibilities for basic and/or applied research. Furthermore, with recent advances in the synthesis of nanostructures, it has become possible to consider not only the size-dependent, but also the shape- and morphology-dependent optical/electrical properties of these systems.

There are several research themes in Kuno’s group. On the optical side, we have recently developed some of the first single nanostructure absorption experiments. This is important since there has been considerable effort on measuring single nanostructure emission over the years. However, not all nanostructures are emissive and there is a tremendous wealth of electronic structure information gained by studying the size dependent absorption of individual nanocrystals. On the synthetic/applied side, we are pursuing new chemistries for making 1D and 2D nanostructures. With the latter system, we have recently developed methods for producing CdSe and TiS2 nanosheets, opening the door to materials of potential interest for photocatalytic applications.

The research in the Kuno group is intrinsically interdisciplinary and spans areas such as physical chemistry, materials chemistry, inorganic chemistry, and even device chemistry/physics.

Awards

Cottrell Teacher Scholar Award, 2006NSF CAREER Award, 2005NRC Postdoctoral Fellowship, 1998Corning Foundation Predoctoral Fellowship, 1996


Draguta, S.; Thakur, S.; Morozov, Y.; Wang, Y.; Manser, J.S.; Kamat, P.V.; Kuno, M. “Spatially non-uniform trap state densities in solution-processed hybrid perovskite thin films.” J. Phys. Chem. Lett. 2016, 7, 715-721.

Morozov Y.; Kuno, M. “Optical constants and dynamic conductivities of single layer MoS2, MoSe2, and WSe2.” Appl. Phys. Lett. 2015, 107, 083103.

Sokolov, D.A.; Morozov, Y.V.; McDonald, M.P.; Vietmeyer, F.; Hodak, J.H.; Kuno, M. “Direct observation of single layer graphene oxide reduction through spatially-resolved, single sheet absorption/emission microscopy.” Nano Lett. 2014, 14(6), 3172-3179.

Wang, Y.X.; Zhukovskyi, M.; Tongying, P.; Tian, Y.; Kuno, M. “Synthesis of Ultrathin and Thickness-Controlled Cu2-xSe Nanosheets via Cation Exchange.” J. Phys. Chem. Lett. 2014, 5 (21), 3608-3613.

Kuno, M. “Tailoring the Inherent Optical and Electrical Properties of Nanostructures.” J. Phys. Chem. Lett. 2014, 5 (21), 3817-3818.

Zhukovskyi, M.; Sanchez-Botero, L.; McDonald, M.P.; Hinestroza, J.; Kuno.K. “Nanowire-Functionalized Cotton Textiles.” ACS Appl. Mater. Interfaces 2014, 6 (4), 2262-2269.

MASARU K. KUNOProfessor

Director of Graduate Admissions(574) 631-0494

[email protected]

A. GRAHAM LAPPINProfessor(574) 631-7820 [email protected]

SRC fellow, University of Leeds, 1977–78 Postdoctoral Research Fellow, University of Leeds, 1977–78Postdoctoral researcher, Purdue University, 1975–77PhD, University of Glasgow, 1975BSc, Inorganic Chemistry, University of Glasgow, 1972

Inorganic Reaction Mechanisms

Lappin’s interests cover both substitution reactions and redox processes of transition metal ion complexes and range from reactions of metalloproteins in biological systems to the corrosion chemistry associated with nuclear reactors. Studies of cooperation between multiple reaction centers in chemical reactions have been a long-standing area of research, particularly those involving multiple electron transfer, coupled electron and ion transfer, and catalysis.

Lappin’s group has investigated phenomena associated with chiral induction in electron transfer and atom transfer reactions involving metal ion complexes and has provided much of the insight required for the interpretation of this effect. The inductions tend to be small, but provide a very sensitive mechanistic probe. They occur quite generally in both outer-sphere and inner-sphere reactions.

Work in this area encompasses developments in molecular and chiral recognition and the characterization of weak interactions between metal complexes. These studies have led to the design of novel chiral ligands and investigations of weak bonding interactions by NMR relaxation and X-ray crystallography. Studies have been extended to reactions involving atom transfer to non-metallic reagents where reactions are catalytic.


Moncada, A.S.; Einschlag, F.S.G.; Prieto, E.D.; Ruiz, G.T.; Lappin, A.G.; Ferraudi, G.J.; Wolcan, E. “Photophysical properties of -Re(I)(CO)(3)(phen) pendants grafted to a poly-4-vinylpyridine backbone. A correlation between photophysical properties and morphological changes of the backbone.” J. Photoch. Photobio. A 2016, 321, 284-296.

Gallagher, M.K.; Oliver, A.G.; Lappin, A.G. “Crystal structure of tris(trans-1,2-diaminocyclohexane-kappa N-2, N’)cobalt(III) trichloride monohydrate.” Acta Crystallogr. E 2016, 72, 49.

Garcia, C.; Diaz, C.; Araya, P.; Isaacs, F.; Ferraudi, G.; Lappin, A.G.; Aguirre, M.J.; Isaacs, M. “Electrostatic self-assembled multilayers of tetrachromatedmetalloporphyrins/polyoxometalate and its electrocatalytic properties in oxygen reduction.” Electrochim. Acta 2014, 146, 819-829.

Ferraudi, G.; Lappin, A.G. “Review: Properties and chemical reactivity of metallo phthalocyanine and tetramethylbenzoannulene complexes grafted into a polymer backbone.” J. Coord. Chem. 2014, 67 (23-24), 3822-3839.

Estiu, G.; Ferraudi, G.; Lappin, A.G.; Ruiz, G.T.; Vericat, C.; Costamagna, J.; Villagran, M. “Photocatalytic reactions of a nickel(II) annulene complex incorporated in polymeric structures.” RSC Advances 2014, 4 (95), 53157-53171.

Lemus, L.; Guerrero, J.; Costamagna, J.; Lorca, R.; Jara, D.H.; Ferraudi, G.; Oliver, A.; Lappin, A.G. “Resolution and chacterization of helicate dimer and trimer complexes of 1,3-bis-(9-methyl-1,10-phenanthrolin-2-yl)propane with copper (I).” Dalton T. 2013, 42 (32), 11426-11435.

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MARYA LIEBERMANProfessor


National Science Foundation postdoctoral fellow, California Institute of Technology, 1994–96

PhD, Chemistry, University of Washington at Seattle, 1994BS, Chemistry, Massachusetts Institute of Technology, 1989

Surface Technology

Lieberman’s interests include the study of how simple precursors assemble into complex structures. At the nanoscopic level, the group studies the self-assembly of DNA nanostructures, the formation of functional self-assembled monolayers, and binding interactions between molecules and surfaces. We have a longstanding collaboration with Gary Bernstein’s group in EE to explore electron-beam lithography as a patterning tool. More recently the group has begun to use engineered paper devices as analytical tools for detection of counterfeit drugs and environmental applications. Students from all four divisions (inorganic, physical, organic, and biochemistry) are welcome to explore research in our group. Many characterization methods are used to get insight into the structure and electronic properties of molecules on surfaces or inside materials. Students are encouraged to contact Lieberman for more up-to-date information on projects.

DNA NanostructuresWe are studying fundamental materials issues for the integration of self-assembling DNA nanostructures (DNA lattices, tiles, or origami) with top-down CMOS fabrication methods. Students with an interest in synthetic chemistry can tackle the integration of non-DNA components with DNA nanostructures, while students with more of a physical or analytical focus can address fundamental questions about the yields, error types, and ultimate utility of self-assembly, or can explore ways to attach DNA origami to unusual substrates.

Ultra-high resolution lithography for patterning of biomolecules and nanoparticlesElectron-beam lithography is used in very high resolution CMOS fabrication processes. We are learning how to use the electron beam to chemically pattern surfaces so that proteins, DNA, or nanoparticles can be guided to bind in specific locations. The ultimate goal is to make nanoelectronic circuits much smaller than can be accessed with lithography alone. Students with a physical/analytical bent and an interest in biochemistry can explore new types of substrates and targets for attachment; applications include sensor development and fundamental studies of biomolecule patterning at the single biomolecule limit.

Paper analytical devicesIn this project, we are developing “smart materials” that can be used by untrained people to carry out a range of chemical and biochemical assays. By engineering the surface chemistry of paper substrates and loading reagents at specific locations, we can carry out dozens of qualitative inorganic and organic tests at once, or program the paper to carry out a titration or spectrophotometric assay. The targets include detection of low-quality or counterfeit pharmaceuticals, pathogens, environmental analysis, and analysis of micronutrients. In collaboration with computer scientists, we are writing image recognition software to evaluate the test outcomes and to map test results across whole regions. Design and prototyping is an integral part of the projects, and travel may be required for field tests in Kenya and Haiti. Current work focuses on synthetic biology as a tool for creating biosensors to embed in the paper, and on techniques for trace (ppm, ppb) analysis in paper-based systems.

Selected Awards

Partners for Progress Prosperity (P3) Award, ACS Joint Great Lakes/Central Region, 2015

Joyce Award for Excellence in Undergraduate Teaching, 2010 Reilly Fellow, 2001-presentNSF CAREER Award, 1998


Myers, N.M.; Strydom, E.E.; Sweet, J.; Spohrer, R.; Dhansay, M.A.; Lieberman, M. “saltPAD: A New Analytical Tool for Monitoring Salt Iodization in Low Resource Settings.” Nanobiomedicine 2016, 3, 5.

Myers, N.M.; Kernisan, E.; Lieberman, M. “Part per million quantification of iodate in fortified salt using a paper device.” Anal. Chem. 2015, 87, 3764-3770.

Weaver, A.A.; Lieberman, M. “Paper Test Cards for Presumptive Testing of Very Low Quality Antimalarial Medications.” Am. J. Trop. Med. Hyg. 2015, 92(6), 17-23.

Weaver, A.; Halweg, S.; Joyce, M.; Lieberman, M.; Goodson, H.V. “Incorporating yeast biosensors into paper-based analytical tools for pharmaceutical analysis.” Anal. Bioanal. Chem. 2015, 407(2), 615-619.

Pillers, M.A.; Shute, R.; Farchone, A.; Linder, K.P.; Doerfler, R.; Gavin, C.; Goss, V.; Lieberman, M. “Preparation of Mica and Silicon Substrates for DNA Origami Analysis and Experimentation.” J. Vis. Exp. 2015, 101, e52972.

LAURIE LITTLEPAGECampbell Family Assistant Professor of Cancer Research(574) [email protected]

Postdoctoral Fellow, University of California, San Francisco 2003-2009

PhD, Cell and Developmental Biology, Harvard University, 2003

BS, Biochemistry, University of Texas at Austin, 1995BS, Molecular Biology, University of Texas at Austin, 1995

Tumor/stroma interaction in mammary gland development and breast cancer progression

In the Littlepage laboratory, our research is focused on the contributions of the epithelium and surrounding microenvironment/stroma to both cancer progression and normal tissue development in the mammary gland and prostate. We use this research to understand the mechanisms of cancer progression in order to develop relevant cancer biomarkers and therapies to prevent or reverse cancer in patients. Currently our projects focus on these topics in breast and prostate cancers.

Background: Cancer malignancies continually adapt to the changing epithelium and the surrounding tumor microenvironment, or stroma, in order to survive and spread outside of the primary tissue. In normal human mammary glands, the epithelium is highly organized. These glands have intact lumens, an intact basement membrane, and surrounding stromal cells. During cancer progression, some of these cells undergo progressive changes. Tumors develop by utilizing normal developmental processes to promote survival and poor prognosis in patients. At each stage of tumor progression, the epithelium becomes exposed to a completely different set of cells and molecules, depending on its neighbors. This microenvironment promotes changes within the epithelium. This context is critical in being able to understand cancer and develop effective therapies.

Experimental Approach: We use integrated biological approaches to understand the contributions of specific genes in vivo at multiple points in cancer progression, spanning from normal mammary development to tumor progression to metastasis to chemotherapy resistance. We both develop and use a combination of mouse and human xenograft in vivo models, cell culture and organotypic cultures, and systems biology approaches to study biomarkers of epithelial plasticity and to determine how these genes drive aberrations in fundamental biological processes, e.g. differentiation state, progenitor cell maintenance, metabolism, and genomic integrity. We also are identifying targeted therapies appropriate for personalized treatment of cancer patients based on these biomarkers. This research is translational and relevant to both cancer prevention and treatment of poor prognosis in cancer patients.

Selected Awards

American Society for Cell Biology Postdoctoral Travel Award, 2011

UCSF Postdoctoral Teaching Fellowship Program, 2007, 2011

American Cancer Society Postdoctoral Fellowship, 2006-2010

Ruth L. Kirschstein National Research Service Award, National Institutes of Health, National Cancer Institute, 2003-2006

Honorable Mention, L’Oreal USA for Women in Science Fellowship Program, 2005


Sawe, R.T.; Kerper, M.; Badve, S.; Li, J.; Sandoval-Cooper, M.; Xie, J.M.; Shi, Z.G.; Patel, K.; Chumba, D.; Ofulla, A.; Prosperi, J.; Taylor, K.; Stack, M.S.; Mining, S.; Littlepage, L.E. “Aggressive breast cancer in western Kenya has early onset, high proliferation, and immune cell infiltration.” BMC Cancer 2016, 16, 204.

Suarez, C.D.; Littlepage, L.E. “Patient-Derived Tumor Xenograft Models of Breast Cancer.” Methods Mol. Biol.2016, 1406, 211-223.

Frietze, S.; O’Geen, H.; Littlepage, L.E.; Simion, C.; Sweeney, C.A.; Farnham, P.J.; Krig, S.R. “Global analysis of ZNF217 chromatin occupancy in the breast cancer cell genome reveals an association with ERalpha.” BMC Genomics 2014, 15, 520.

Kessenbrock, K.; Dijkgraaf, G.J.P.; Lawson, D.A.; Littlepage, L.E.; Shahi, P.; Pieper, U.; Werb, Z. “A Role for Matrix Metalloproteinases in Regulating Mammary Stem Cell Function via the Wnt Signaling Pathway.” Cell Stem Cell 2013, 13 (3), 300-313.

Littlepage, L.E.; Adler, A.S.; Kouros-Mehr, H.; Huang, G.; Chou, J.; Krig, S.R.; Griffith, O.L.; Korkola, J.E.; Qu, K.; Lawson, D.A.; Xue, Q.; Sternlicht, M.D.; Dijkgraaf, G.J.; Yaswen, P.; Rugo, H.S.; Sweeney, C.A.; Collins, C.C.; Gray, J.W.; Chang, H.Y.; Werb, Z. “The Transcription Factor ZNF217 is a Prognostic Biomarker and Therapeutic Target during Breast Cancer Progression.” Cancer Discov. 2012, 2(7), 638-651.

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SHAHRIAR MOBASHERYNavari Family Professor

in Life Sciences(574) 631-2933

[email protected]

National Institutes of Health postdoctoral fellow, Rockefeller University, 1986–88

PhD, Chemistry, University of Chicago, 1985BS Chemistry and Biological Sciences, University of

Southern California, 1981

Bioorganic Chemistry

The research interests of Mobashery’s laboratory center on bioorganic chemistry, organic synthesis, protein chemistry, enzymology, and computational sciences. The research carried out in the laboratory employs a multidisciplinary approach to solve problems at the interface of chemistry and biology. Biologically active molecules are designed and synthesized in the laboratory to test important concepts in the mechanisms of action of antibiotics and enzyme inhibitors as potential pharmaceutical agents.

The research interests in the group encompass studies of mechanisms of resistance to antibiotics and the means to circumvent them, development of novel antibiotics, studies of the mechanism of action of these antibiotics, and investigations of complex microbial systems such as the outer membrane and the cell wall. In non-microbial systems, the group is also interested in the molecular mechanisms of a series of diseases of the extracellular matrix, such as idiopathic pulmonary fibrosis, diabetic wound healing, and stroke.

AwardsResearch Achievement Award, University of Notre Dame,

2012Astellas USA Foundation Award of the American Chemical

Society, 2007Fellow of the American Academy for the Advancement of

Science (AAAS), elected 2007Honorary Charter Member of the Argentinian Society for

Organic Chemistry, 2003–presentCharles H. Gershenson Distinguished Fellow, 1999–2001


Lee, M.; Dhar, S.; De Benedetti, S.; Hesek, D.; Boggess, B.; Blazquez, B.; Mathee, K.; Mobashery, S. “Muropeptides in Pseudomonas aeruginosa and their Role as Elicitors of β-Lactam-Antibiotic Resistance.”Angew. Chem. Int. Ed. 2016, 55(24), 6882-6886.

Wang, H.; Desek, D.; Lee, M.; Lastochkin, E.; Oliver, A.G.; Chang, M.; Mobashery, S. “The Natural Product Essramycin and Three of Its Isomers Are Devoid of Antibacterial Activity.” J. Nat. Prod. 2016, 79(4), 1219-1222.

Lee, M.; Dominguez-Gil, T.; Hesek, D.; Mahasenan, K.V.; Lastochkin, Hermoso, J.A.; Mobashery, S. “Turnover of Bacterial Cell Wall by SltB3, a Multidomain Lytic Transglycosylase of Pseudomonas aeruginosa.” ACS Chem. Biol. 2016, 11(6), 1525-1531.

Leemans, E.; Mahasenan, K.V.; Kumarasiri, M.; Spink, E.; Ding, D.; O’Daniel, P.I.; Boudreau, M.A.; Lastochkin, E.; Testero, S.A.; Yamaguchi, T.; Lee, M.; Hesek, D.; Fisher, J.F.; Chang, M.; Mobashery, S. “Three-dimensional QSAR analysis and design of new 1,2,4-oxadiazole antibacterials.” Bioorg. Med. Chem. Lett. 2016, 26(3), 1011-1015.

Janardhanan, J.; Meisel, J.E.; Ding, D.; Schroeder, V.A.; Wolter, W.R.; Mobashery, S.; Chang, M. “In Vitro and In Vivo Synergy of the Oxadiazole Class of Antibacterials with β-Lactams.” Antimicrob. Agents Chemother. 2016, 60(9), 5581-5588.

Bouley, R.; Ding, D.; Peng, Z.; Bastian, M.; Lastochkin, E.; Song, W.; Suckow, M.A.; Schroeder, V.A.; Wolter, W.R.; Mobashery, S.; Chang, M. “Structure-Activity Relationship for the 4(3H)-Quinazolinone Antibacterials.” J. Med. Chem. 2016, 59(10), 5011-5021.

JOHN PARKHILLAssistant Professor(574) 631-2696 [email protected]

Postdoctoral fellow, chemical physics, Harvard University, 2010–13PhD, Theoretical Chemistry, University of California, Berkeley, 2010BS, Mathematics, Chemistry, University of Chicago, 2005

New Methods and Applications of Electronic Structure Theory

Our ability to calculate properties of molecular systems using only the fundamental physics governing them has grown tremendously from computational art into a predictive tool. Geometries and the thermodynamics of chemical reactions can be accurately computed using electronic structure theory. Many of the approximations that make ground state electronic structure robust are naturally less successful beyond the regime of static properties. Errors of excited state energies calculated with the best approaches at our disposal today are orders of magnitude larger than those we expect for ground state reaction enthalpies. Simulations of coupled electron-nuclear dynamics, which could help design better batteries and photovoltaics, are currently too expensive to compute atomistically for most timescales of interest. We can leverage the exponential growth of computational resources to solve these problems with new theories.

My group makes predictive models of electronic dynamics with theory and software, and we apply these tools to understand and design materials that harness electronic energy. Quantum many-body correlation is important whenever electrons rearrange themselves, as they do during charge-transport, and is one target for new theories. We also develop new methods to describe how energy escapes from electronic excited states. The thermal environment modifies the nature of the states themselves, imbuing them with lifetimes and vibronic features that are absent from typical time-dependent density functional calculations.

Photovoltaic materials provide an excellent platform to test our models. Several new materials harness light more efficiently in multi-exciton processes that pass through quantum superposition states. The nature of these electronic states is a matter of vibrant debate. They are of interest because they can exceed classical limits of photovoltaic efficiency and are an unusually clear demonstration of quantum many-body effects. Designing multi-exciton materials by directly comparing to the information from ultrafast non-linear spectroscopy is one of our long-term goals. My students gain experience in developing theory, numerical computation, and chemical physics.


Nguyen, T.S.; Parkhill, J.A. “Nonradiative Relaxation in Real-time Electronic Dynamics OSCF2: Organolead Triiodid Perovskite.” J. Phys. Chem. A 2016, just accepted.

Nguyen, T.S.; Koh, J.H.; Lefelhocz, S.; Parkhill, J.A. “Black-Box, Real-Time Simulations of Transient Absorption Spectroscopy.” J. Phys. Chem. Lett. 2016, 7(8), 1590-1595.

Yao, K; Parkhill, J.A. “Kinetic Energy of Hydrocarbons as a Function of Electron Density and Convolutional Neural Networks.” J. Chem. Theory Comput. 2016, 12(3), 1139-1147.

Nguyen, T.S.; Parkhill, J.A. “Nonadiabatic Dynamics for Electrons at Second-Order: Real-Time TDDFT and OSCF2.” J. Chem. Theory Comput. 2015, 11 (7), 2918-2924.

Nguyen, T.S.; Nanguneri, R.; Parkhill, J.A. “How electronic dynamics with Pauli exclusion produces Fermi-Dirac statistics.” J. Chem. Phys. 2015, 142, 134113.

McClean, J.R.; Parkhill, J.A.; Aspuru-Guzika, A. “Feynman’s clock, a new variational principle, and parallel-in-time quantum dynamics.” P. Natl. Acad. Sci. USA 2013, 110 (41), E3901-3909.

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JEFFREY W. PENGAssociate Professor


Postdoctoral fellowship, ETH-Zürich, 1993–94PhD, Biophysics, University of Michigan, 1993BS, Applied and Engineering Physics, Cornell

University, 1987

Biophysics: Protein and Small-Molecule Dynamics, Receptor-Ligand Interactions, and NMR Methods Development

Understanding the influence of molecular dynamics on the affinity and evolution of biomolecular interactions is an outstanding problem in biophysics. Peng’s research attacks this problem at the atomic level, principally through multidimensional Nuclear Magnetic Resonance (NMR) spectroscopy and computation. The general aim is to develop a more fundamental understanding of protein evolution and drug design that includes the inherent flexibility of biopolymers and their ligands. The NMR studies are complemented by computational chemistry, calorimetry, and collaborations with protein crystallographers and synthetic bioorganic chemists.

A major focus is revealing the atomic basis for intra-protein communication (allostery) between distinct functional sites within signaling proteins relevant for cancer and antibiotic resistance. Allosteric communication often plays a key role in protein signaling mechanisms. Recent NMR and computational studies by the Peng group suggest that proteins can use networks of dynamic residues for allosteric communication. Mapping these dynamic networks helps expose new allosteric binding sites for inhibitor design, and helps predict sites of drug resistant mutations. These studies also involve methods development: in particular, the Peng group seeks to expand the NMR and computational tools to identify and describe collective motions over broad time scales.

A second major focus is exploiting intrinsic molecular flexibility in ligand and drug design. This includes developing methods for “Flexibility-Activity-Relationships”, which include both NMR and computational methods. The goal is to explore the potential for strategic ligand flexibility to thwart drug resistance and enhance drug delivery.


Wang, X.S.; Mahoney, B.J.; Zhang, M.L.; Zintsmaster, J.S.; Peng, J.W. “Negative Regulation of Peptidyl-Prolyl Isomerase Activity by Interdomain Contact in Human Pin1.” Structure 2015, 23(12), 2224-2233.

Staude, M.W.; Frederick, T.E.; Natarajan, S.V.; Wilson, B.D.; Tanner, C.E.; Ruggiero, S.T.; Mobashery, S.; Peng, J.W. “Investigation of Signal Transduction Routes within the Sensor/Transducer Protein BlaR1 of Staphylococcus aureus.” Biochemistry 2015, 54(8), 1600-1610.

Frederick, T.E.; Wilson, B.D.; Cha, J.; Mobashery, S.; Peng, J.W. “Revealing Cell-Surface Intramolecular Interactions in the BlaR1 Protein of Methicillin-Resistant Staphylococcus aureus by NMR Spectroscopy.”Biochemistry 2014, 53 (1), 10-12.

Mercedes-Camacho, A.Y.; Mullins, A.B.; Mason, M.D.; Xu, Gy.G.; Mahoney, B.J.; Wang, X.S.; Peng, J.W.; Etzkorn, F.A. “Kinetic Isotope Effects Support the Twisted Amide Mechanism of Pin1 Peptidyl-Prolyl Isomerase.”Biochemistry 2013, 52 (44), 7707-7713.

Wilson, K.A.; Bouchard, J.J.; Peng, J.W. “Interdomain Interactions Support Interdomain Communication in Human Pin1.” Biochemistry 2013, 52 (40), 6968-6981.

Peng, J.W. “Exposing the Moving Parts of Proteins with NMR Spectroscopy.” J. Phys. Chem. Lett. 2012, 3 (8), 1039-1051.

VICTORIA A. PLOPLISResearch Professor(574) [email protected]

Postdoctoral fellow, Scripps Research Institute, 1982-84PhD, Biochemistry, University of Notre Dame, 1981BA, Biology/Chemistry, Rosary College, 1975

Biology and Biochemistry of the Fibrinolytic Pathway

The fibrinolytic system is composed of the zymogen, plasminogen (Pg); its active enzyme, plasmin (Pm); the plasminogen activators, tissue plasminogen activator (tPA) and urokinase (uPA); and relevant inhibitors plasminogen activator inhibitor-1 (PAI-1) and α2-antiplasmin. This system has been implicated in playing a pivotal role in numerous physiological processes. Due to the ability of plasmin to degrade fibrin, the fibrinolytic system plays an essential role in the prevention of thrombosis and maintenance of vascular patency. The ability of plasmin to directly degrade matrix protein, to activate other matrix degrading proteases and the existence of cellular receptors for components of the fibrinolytic system also implicates this pathway in localized proteolytic processes involved in normal cell migration, tissue remodeling, wound healing, and angiogenesis. In addition, it’s believed that the fibrinolytic system is involved in pathological processes where uncontrolled expression of proteolytic activity occurs, viz., tumor invasion and metastasis. However, much of the evidence for these diverse roles is surmised from in vitro studies and lacks firm biological confirmation. Studies utilizing mice deficient for components of this pathway have already begun to challenge a number of the perceived roles of the fibrinolytic system. In addition, the lack of a more severe thrombotic phenotype and the occurrence of delayed clot lysis in mice deficient for Pg (PG-/-), would appear to support involvement of nonplasmin-mediated fibrinolytic processes for maintaining some degree of vascular patency and, most probably, survival in these deficient mice, possibly due to leukocyte elastases.

Utilizing mice deficient for components of the fibrinolytic system, our laboratory is currently testing hypothesized functions of this pathway when physiologically challenged. Specifically, we are assessing its role in inflammation and diseases associated with inflammation, viz., asthma, atherosclerosis, pulmonary and cardiac fibrosis, as well as other physiological and pathophysiological processes in which cell migration is an essential event, viz., tumor growth, metastasis and angiogenesis. Additionally, we are isolating primary arterial and venous endothelial cells from these gene deficient mice in order to determine altered endothelial cell functions that may contribute to changes in angiogenesis.

Honors and Awards

NIH study section (HT) regular member, 2005–2010Associate Editor, Current Drug Targets, 2002–presentCouncil Member, International Society of Fibrinolysis and

Proteolysis, 2008–presentElected fellow, Council on Atherosclerosis, Thrombosis,

and Vascular Biology (American Heart Association), 1998–present

James A. Shannon NIH Director’s Award, 1996–1997John Hickam Fellow, American Heart Association (Indiana

Affiliate), 1981–82Kappa Gamma Pi; National Catholic College Women’s Honor

Society, 1975–present


Yasui, H.; Donahue, D.L.; Walsh, M.; Castellino, F.J.; Ploplis, V.A. “Early coagulation events induce acute lung injury in a rat model of blunt traumatic brain injury.” Am. J. Physiol.-Lung C. 2016, 311(1), L74-L86.

Bao, Y.J.; Liang, Z.; Mayfield, J.A.; Donahue, D.L.; Carothers, K.E.; Lee, S.W.; Ploplis, V.A.; Castellino, F.J. “Genomic Characterization of a Pattern D Streptococcus pyogenes emm53 Isolate Reveals a Genetic Rationale for Invasive Skin Tropicity.” J. Bacteriol. 2016, 198(12), 1712-1724.

Mamczak, C.N.; Maloney, M.; Fritz, B.; Boyer, B.; Thomas, S.; Evans, E.; Ploplis, V.A.; Castellino, F.J.; McCollester, J.; Walsh, M. “Thromboelastography in Orthopaedic Trauma Acute Pelvic Fracture Resuscitation: A Descriptive Pilot Study.” J. Orthop. Trauma 2016, 30(6), 299-305.

Agrahari, G.; Liang, Z.; Glinton, K.; Lee, S.W.; Ploplis, V.A.; Castellino, F.J. “Streptococcus pyogenes Employs Strain-dependent Mechanisms of C3b Inactivation to Inhibit Phagocytosis and Killing of Bacteria.” J. Biol. Chem. 2016, 291(17), 9181-9189.

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WILLIAM F. SCHNEIDERH. Clifford and Evelyn A. Brosey

Concurrent Professor of Engineering(574) 631-8754

[email protected]

PhD, Chemistry, Ohio State University, 1991BSc, Chemistry, University of Michigan, Dearborn, 1986

Computational Catalysis Environmental Chemistry

Schneider’s group applies state-of-the-art first-principles molecular simulation tools, based primarily on density functional theory (DFT), to study a range of problems in energy-related catalysis and environmental protection. These quantum-mechanics-based calculations take advantage of some of the latest and most powerful computers available to produce accurate predictions of chemical structure, energetics, and reactivity for systems that were impossible to study even just a few years ago. Statistical thermodynamics and kinetics provide the links to macroscopic prediction. The simulations are coupled with simple but powerful concepts of chemical structure and bonding—key to both the effective use of the tools and extraction of useful physical insight. The group partners closely with experimental groups both to validate results and to provide an avenue for their rapid application.

One current area of emphasis is the development of quantitative models of reactivity at solid surfaces. DFT calculations are used to model the adsorption and transformation of molecules at a surface, to understand adsorbate-surface and adsorbate-adsorbate interactions that govern these transformations, and ultimately to integrate this information into predictive kinetic models of catalytic reactivity. Applications span the range from the catalytic remediation of nitrogen oxides (NOx) from combustion emissions and water to catalytic transformations of CO and CO2. Room temperature ionic liquids (RTILs) are a relatively new type of reaction medium, and the group is similarly using DFT models to guide the design of RTILs with desirable reactivity, for instance towards CO2.

Understanding gained at the molecular level allows us to better control—and ultimately to tailor—chemical systems to perform functions more cleanly, efficiently, and durably. The research group is highly multidisciplinary, cutting across the traditional boundaries of chemical engineering, chemistry, surface science, physics, environmental science, materials science, and the emerging field of nanoscience.

Awards

Fellow of the American Association for the Advancement of Science (AAAS), 2011

BP Foundation Outstanding Teacher Award, College of Engineering, University of Notre Dame, 2009

Professional Growth and Scholarship Award, Alumni Society, University of Michigan-Dearborn, 2008


Paolucci, C.; Parekh, A.A.; Khurana, I.; Di Iorio, J.R.; Li, H.; Caballero, J.D.A.; Shih, A.J.; Anggara, T.; Delgass, W.N.; Miller, J.T.; Ribeiro, F.H.; Gounder, R.; Schneider, W.F. “Catalysis in a Cage: Condition-Dependent Speciation and Dynamics of Exchanged Cu Cations in SSZ-13 Zeolites.” J. Am. Chem. Soc. 2016, 138(18), 6028-6048.

Stephenson, C.A.; O’Brien, W.A.; Qi, M.; Penninger, M.; Schneider, W.F.; Wistey, M.A. “Band Anticrossing in Dilute Germanium Carbides Using Hybrid Density Functionals.” J. Electron. Mater. 2016, 45(4), 2121-2126.

Lee, T.B.; Oh, S.; Gohndrone, T.R.; Morales-Collazo, O.; Seo, S.; Brennecke, J.F.; Schneider, W.F. “CO2Chemistry of Phenolate-Based Ionic Liquids.” J. Phys. Chem. B 2016, 120(8), 1509-1517.

Herder, L.M.; Bray, J.M.; Schneider, W.F. “Comparison of cluster expansion fitting algorithms for interactions at surfaces.” Surf. Sci. 2015, 640, 104-111.

Penninger, M.W.; Kim, C.H.; Thompson, L.T.; Schneider, W.F. “DFT Analysis of NO Oxidation Intermediates on Undoped and Doped LaCoO3 Perovskite.” J. Phys. Chem. C 2015, 119(35), 20488-20494.

Bray, J.M.; Schneider, W.F. “First-Principles Analysis of Structure Sensitivity in NO Oxidation on Pt.” ACS Catal.2015, 5 (2), 1087-1099.

ZACHARY SCHULTZAssociate Professor(574) 631-1853 [email protected]

Research Fellow, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, 2007–2009

NRC Postdoctoral Fellow, National Institute of Standards and Technology, 2005–2007

PhD, Analytical Chemistry, University of Illinois at Urbana-Champaign, 2005

BS, Chemistry,The Ohio State University, 2000

Label-Free Detection and Imaging

Research in the Schultz laboratory focuses on understanding how the spatial organization of molecules affects their behavior. We utilize laser spectroscopy, including nonlinear spectroscopic methods, and also spectroscopic imaging modalities such as Raman near-field scanning optical microscopy, which is capable of vibrational spectroscopic imaging with a spatial resolution of tens of nanometers. We are further investigating signal enhancements associated with metallic nanostructures to attain high-sensitivity measurements. Our goal is to develop label-free methods that avoid artifacts and challenges associated with chemical modifications.

One area where molecular organization plays an important role is the behavior observed in cellular membranes. We are interested in understanding how the organization of molecules in biomembranes impact biomedical issues such as dysfunctional cellular pathways that cause disease, viral and bacterial infection, and drug delivery. These interactions occur at the nanometer length scale and are sensitive to chemical modification, necessitating the development of new label-free methods.

A second area involves understanding how chemical heterogeneity affects reactivity. Bi-metallic nanoparticles, used as catalysts in fuel cells, often show chemical activity that the individual components

do not. Understanding the molecular interactions associated with these composite materials is important for developing new sources of energy. Methods being developed in our laboratory have the potential to offer new insights into these processes.


Xiao, L.; Wang, H.; Schultz, Z.D. “Selective Detection of RGD-Integrin Binding in Cancer Cells Using Tip Enhanced Raman Scattering Microscopy.” Anal. Chem. 2016, 88(12), 6547-6553.

Bailey, K.A.; Schultz, Z.D. “Tracking Bulk and Interfacial Diffusion Using Multiplex Coherent Anti-Stokes Raman Scattering Correlation Spectroscopy.” J. Phys. Chem. B 2016, 120(27), 6819-6828.

Riordan, C.M.; Jacobs, K.T.; Negri, P.; Schultz, Z.D. “High Throughput Chemical Profiling in Urine by SERS.” Faraday Discuss. 2016, 187, 473-484.

Nguyen, A.; Schultz, Z.D. “Quantitative online sheath-flow surface enhanced Raman spectroscopy detection for liquid chromatography.” Analyst 2016, 141(12), 3630-3635.

Kwasnieski, D.T.; Wang, H.; Schultz, Z.D. “Alkyl-Nitrile Adlayers as Probes of Plasmonically Induced Electric Fields.” Chem. Sci. 2015, 6(8), 4484-4494.

Jacobs, K.T.; Schultz, Z.D. “Increased SERS Detection Efficiency for Characterizing Rare Events in Flow.” Anal. Chem. 2015, 87(16), 8090-8095.

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MARGARET SCHWARZAdjunct Professor


MD, University of Missouri Six-Year Medical School, 1987BA, Biology, University of Missouri, Kansas City, 1986

Computational Catalysis Environmental Chemistry

The Schwarz laboratory uses transgenic mice, three dimensional cell culture, in vivo tumor, and lung developmental models to determine mechanisms by which the vascular mediators regulate cardio-pulmonary development and regeneration following injury and cancer progression.

Our main interests are the role that the anti-angiogenic mediator Endothelial Monocyte Activating Polypeptide II (EMAP II, also known as AIMP-1, Scye-1, and p43) has in lung, cardiac, and tumor development. On the cell surface, EMAP II undergoes proteolytic cleavage to generate an extracellular ≈22-kDa C-terminal peptide that functions as an anti-angiogenic protein through inhibition of endothelial cell adhesion to fibronectin, blockade of fibronectin matrix assembly via α5β1 integrin, and interference with vascular endothelial growth factor (VEGF) induced pro-angiogenic signaling.

Earlier studies identified a direct interaction between vascular growth factors and the regulation of tissue formation. Using pulmonary developmental models, we have shown that vascular growth factors can also impact epithelial –mesenchymal transdifferentiation, extracellular matrix deposition, and airway simplification resulting in physiologic changes in pulmonary function. Currently, our studies focus on the mechanisms that modulate cardio-pulmonary vascular growth and the subsequent impact that the vasculature has on alveolar growth by examining vessel mediation of interstitial lung disease, deposition of the extracellular matrix protein, and epithelial cell proliferation.

By using pancreatic cancer models (intraperitoneal and subQ), targeted multi-drug therapy strategies are utilized to determine the role that anti-angiogenic factors alone and in combination with chemotherpeutic agents have in regulating tumor cell proliferation and microenvironment including the dense tumor stroma layer, extracellular matrix deposition and vessel formation. Recent studies utilizing this strategy demonstrated that this multi-target approach is effective and superior to current conventional chemotherapeutic strategies.

Awards

Fellow of the American Association for the Advancement of AOA, 2004

Clinician Scientist Award, American Heart Association, 1993-1998

Finalist for the Louis N. Katz Basic Science Research Prize, American Heart Association1995

Dr. Edward Livingston Trudeau Scholar, American Lung Association, 1998


Lee, D.D.; Lal, C.V.; Persad, E.A.; Lowe, W.; Schwarz, A.M.; Awasthi, N.; Schwarz, R.E.; Schwarz, M.A. “EMAP II Mediates Macrophage Migration in Development of Hyperoxia-Induced Lung Disease of Prematurity.” Am. J. Respir. Cell Mol. Biol. 2016, PMID:27254784.

Lee, D.D.; Schwarz, M.A. “Adapted approach to profile genes while reconciling Vegf-a mRNA expression in the developing and injured lung.” Am. J. Physiol. - Lung C. 2015, 308 (12), L1202-1211.

Xu, H.M.; Malinin, N.L.; Awasthi, N.; Schwarz, R.E.; Schwarz, M.A. “The N Terminus of Pro-endothelial Monocyte-activating Polypeptide II (EMAP II) Regulates Its Binding with the C Terminus, Arginyl-tRNA Synthetase, and Neurofilament Light Protein.” J. Biol. Chem. 2015, 290 (15), 9753-9766.

Awasthi, N.; Hinz, S.; Brekken, R.A.; Schwarz, M.A.; Schwarz, R.E. “Nintedanib, a triple angiokinase inhibitor, enhances cytotoxic therapy response in pancreatic cancer.” Cancer Lett. 2015, 358 (1), 59-66.

Yuan, C.; Yan, L.; Solanki, P.; Vatner, S.F.; Vatner, D.E.; Schwarz, M.A. “Blockade of EMAP II protects cardiac function after chronic myocardial infarction by inducing angiogenesis.” J. Mol. Cell. Cardiol. 2015, 79, 224-231.

Awasthi, N.; Zhang, C.H.; Schwarz, A.M.; Hinz, S.; Schwarz, M.A.; Schwarz, R.E. “Enhancement of Nab-Paclitaxel Antitumor Activity through Addition of Multitargeting Antiangiogenic Agents in Experimental Pancreatic Cancer.” Mol. Cancer Ther. 2014, 13(5), 1032-1043.

ANTHONY S. SERIANNIProfessor(574) 631-7807 [email protected]

Postdoctoral research associate, Cornell University, 1980–82

PhD, Biochemistry, Michigan State University, 1980BS, Biochemistry, Albright College, 1975

Structural Glycobiology

The Serianni laboratory is interested in elucidating the biochemical and biophysical properties of saccharides, either free in solution or appended to biologically important proteins. Recent work has focused on structural studies of oligosaccharides appended to the human N-linked glycoproteins, CD2 and IgG.

Present efforts are directed at developing new experimental and theoretical tools to elucidate oligosaccharide conformations and dynamics using an interdisciplinary strategy. The strategy involves (1) chemical and chemo-enzymic synthesis with stable isotopes (13C, 2H, 15N), (2) modern NMR techniques applicable to isotopically labeled molecules, (3) ab initio molecular orbital calculations (DFT) and molecular dynamics simulations (MD) to assist in correlating specific NMR parameters with solution structure, and (4) x-ray crystallography.

An example of recent work involves the use of trans-glycoside NMR J-couplings to evaluate linkage conformation and dynamics. Six or more NMR J-couplings exist across these linkages and recent parametrizations and population analyses using a new computer program, MA’AT, have provided unique quantitative information about C-O rotamer populations in these linkages. This approach is applicable to all linkages in complex oligosaccharides and provides a novel means of evaluating the role of structural context in determining linkage conformation.

Recent work has shown that some NMR J-couplings in saccharides are sensitive to two molecular torsion angles and can thus be dual parametrized (Figure 1). This discovery allows determinations of correlated conformation about both torsions in solution. The methodology has been validated through studies of exocyclic hydroxymethyl conformation in simple glycosides and is being extended to 1,6-glycosidic linkages.

Awards

Fellow, Royal Society of Chemistry, 2012Fellow, American Association for the Advancement of

Science, 2010American Chemical Society, Melville L. Wolfrom Award in

Carbohydrate Chemistry, 2006John A. Boezi Memorial Alumnus Award, Michigan State

University, 2001Distinguished Alumnus Award, Albright College, 1996American Chemical Society, Horace S. Isbell Award in

Carbohydrate Chemistry, 1988


Zhang, W.; Pan, Q.; Serianni, A.S. “A chemical synthesis of a multiply 13C-labeled hexasaccharide: a high-mannose N-glycan fragment.” J. Labelled Comp. Radiopharm. 2016, epub ahead of print.

Zhang, W.; Zhao, S.; Serianni, A.S. “Labeling monosaccharides with stable isotopes.” Methods Enzymol. 2015, 565, 423-458.

Klepach, T.; Zhao, H.; Hu, X.; Zhang, W.; Stenutz, R.; Hadad, M.J.; Carmichael, I.; Serianni, A.S. “Informing saccharide structural NMR studies with density functional theory calculations.” Methods in Molecular Biology 2015, 1273, 289-331.

Larson, D.J.; Middle, L.; Vu, H.; Zhang, W.H.; Serianni, A.S.; Duman, J.; Barnes, B.M. “Wood frog adaptations to overwintering in Alaska: new limits to freezing tolerance.” J. Exp. Biol. 2014, 217(12), 2193-2200.

Zhang, W.H.; Oliver, A.G.; Vu, H.M.; Duman, J.G.; Serianni, A.S. “Methyl 4-O-beta-D-xylopyranosyl beta-D-mannopyranoside, a core disaccharide of an antifreeze glycolipid.” Acta Crystallogr. C 2013, 69(9), 1047.

Zhang, W.H.; Hu, X.S.; Carmichael, I.; Serianni, A.S. “Methyl [C-13]Glucopyranosiduronic Acids: Effect of COOH Ionization and Exocyclic Structure on NMR Spin-Couplings.” J. Org. Chem. 2012, 77(21), 9521-9534.

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SLAVI C. SEVOVProfessor


Postdoctoral fellow, University of Chicago, 1993–95PhD, Iowa State University, 1993MS, Chemistry, University of Sofia, 1985BS, Chemistry, University of Sofia, 1983

Inorganic and Solid-State Chemistry

Sevov’s research emphasizes the synthesis and characterization of novel compounds and covers two major areas of interest: (1) functionalization and oligomerization of main-group clusters in solutions, and (2) hybrid organic-inorganic materials with open-framework structures.

The interest in the first area developed from the discovery of unprecedented deltahedral clusters of Si9

4-, Ge94-, Sn9

4-, and Pb9

4- in simple solid-state compounds with alkali metals as countercations, Rb4Ge9 for example. The clusters can be extracted in ethylediamine or liquid ammonia solutions, and our research is aimed at studying their reactivity. The goal is to synthetically explore these species and their reactivity, investigate the crystal and electronic structures of the compounds and study their physical properties. Specifically, we have studied extensively the reactivity of Ge9

4- towards various reagents and have found, to our and many other people’s surprise, that they can be readily functionalized with various groups and form mono-, di-, tri-, and tetra-substituted species [Ge9R]3-, [Ge9R2]2-, [Ge9R3]–, and [Ge9R4]0 (shown in the Figure) respectively.

Sevov’s group is also interested in compounds with open-framework structures. They have synthesized the first such open-framework borophosphate and the first borophosphate templated by a transition metal complex. Also synthesized was the first large borophosphate polyoxometalate and its phenyl functionalized version. Other systems of interest include extended frameworks of transition-metals connected by organic linkers with two or more functional groups, such as di-phosphonates, carboxylatephosphonates, boronate-phosphonates, and carboxylate-boronates.

Awards

Exxon-Mobil Faculty Award in Solid State Chemistry, 1999NSF CAREER award, 1997 Camille and Henry Dreyfus New Faculty Award, 1995


Perla, L.G.; Sevov, S.C. “A Stannyl-Decorated Zintl Ion [Ge18Pd3(SniPr3)6]2-: Twinned Icosahedron with a Common Pd3-Face or Eighteen-Vertex Hypho-Deltahedron with a Pd3-Triangle Inside?” J. Am. Chem. Soc. 2016, 138(31), 9795-9798.

Li, F.; Munoz-Castro, A.; Sevov, S.C. “[(Me3Si)Si]3EtGe9Pd(PPh3), a Penta-Functionalized Deltahedral Zintl Cluster: Synthesis, Structure, and Solution Dynamics.” Angew. Chem. Int. Ed. 2016, 55, 8630.

Perla, L.G.; Sevov, S.C. “Cluster Fusion: Face-Fused Nine-Atom Deltahedral Clusters in [Sn14Ni(CO)]4-n” Angew. Chem. Int. Ed. 2016, 55, 6721.

Perla, L.G.; Oliver, A.G.; Sevov, S.C. “Bi7(3-): The Missing Family Member, Finally Isolated and Characterized.” Inorg. Chem. 2015, 54(3), 872-875.

Li, F.; Sevov, S.C. “Synthesis, Structures, and Solution Dynamics of Tetrasubstituted Nine-Atom Germanium Deltahedral Clusters.” J. Am. Chem. Soc. 2014, 136(34), 12056-12063.

Munoz-Castro, A.; Sevov, S.C. “Trimetallic deltahedral Zintl ions [Sn9-m-nGemBin]((4-n)-) for n=1-4 and m=0-(9-n): a theoretical survey with prediction and rationalization of the possible structures.” Phys. Chem. Chem. Phys. 2013, 15(3), 986-991.

BRADLEY D. SMITHEmil T. Hofman ProfessorDirector, Notre Dame Integrated Imaging Facility(574) 631-8632 [email protected]

Postdoctoral researcher, Columbia University, 1990–91Postdoctoral researcher, Oxford University, 1988–89PhD, Organic Chemistry, Pennsylvania State University, 1988BS, Chemistry, University of Melbourne, 1983

Supramolecular Chemistry and Molecular Imaging

The research led by Smith is multidisciplinary and encompasses topics, such as synthetic organic chemistry, molecular recognition, fluorescence microscopy, and whole animal imaging of diseases models.

A major goal is to develop molecular probes for biomedical imaging. In contrast to conventional imaging methods, which display anatomical differences, molecular imaging employs a molecular probe that emits a signal only from the site of probe localization or activation. New classes of optical and nuclear probes are designed to locate tumors or bacterial infection in living animals. The cancer imaging probes will allow early identification of cancer and facilitate next-generation fluorescence guided surgery. Another series of molecular probes have highly selective bacteria recognition properties. The bacterial imaging technology provides new methods of evaluating antibiotic therapy in live animals, new methods of monitoring the progress of bacterial infections, and new methods of detecting bacterial contamination in the environment.

A notable discovery is a family of interlocked molecules called squaraine-rotaxanes, which have many potential applications as extremely bright and stable fluorescent Near-IR dyes. An offshoot of this work is the development of novel self-illuminating nanoparticles for chemiluminescence bioimaging.

Awards

Science Advisory Committee, Research Corporation for Science Advancement, 2011-2013

Fellow, Royal Society of Chemistry, 2012Fellow, American Association for Advancement of Science,

2011NSF Early Career grantee, 1995 Research Corporation Cottrell Scholar, 1994


Rice, D.R.; Clear, K.J.; Smith, B.D. “Imaging and therapeutic applications of zinc(II)-dipicolylamine molecular probes for anionic biomembranes.” Chem. Commun. 2016, 52, 8787-8801.

Peck, E.M.; Battles, P.M.; Rice, D.R.; Roland, F.M.; Norquest, K.A.; Smith, B.D. “Pre-assembly of Near-infrared Fluorescent Multivalent Molecular Probes for Biological Imaging.” Bioconjugate Chem. 2016, 27, 1400-1410.

Liu, W.; Peck, E.M.; Smith, B.D. “High Affinity Macrocycle Threading by a Near-Infrared Croconaine Dye with Flanking Polymer Chains.” J. Phys. Chem. B 2016, 120, 995-1001.

Guha, S.; Shaw, G.K.; Mitcham, T.M.; Bouchard, R.R.; Smith, B.D. “Croconaine Rotaxane for Acid Activated Photothermal Heating and Ratiometric Photoacoustic Imaging of Acidic pH.” Chem. Commun. 2016, 52, 120-123.

Smith, B.D. “Smart Molecules for Imaging, Sensing and Health (SMITH).” Beilstein J. Org. Chem. 2015, 11, 2540-2548.

Rice, D.R.; Plaunt, A.J.; Turkyilmaz, S.; Smith, M.; Wang, Y.; Rusckowski, M.; Smith, B.D. “Evaluation of [111In]-Labeled Zinc-Dipicolylamine Tracers for SPECT Imaging of Bacterial Infection.” Mol. Imaging Biol. 2015, 17 (2), 204-213.

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SHARON STACKKleiderer-Pezold Professor of Biochemistry

Ann F. Dunne & Elizabeth Riley Director, Harper Cancer Research Institute


Postdoctoral Research Associate, Duke University Medical Center, 1989-1991

PhD, Biochemistry, University of Louisville, 1989MS, Biochemistry, East Tennessee State, 1985BS, Biochemistry, Clemson University, 1981

Biochemistry

The ability to invade host tissues and metastasize is the major cause of cancer-related death. During tumor invasion, metastasizing cells disrupt normal cell-cell and cell-matrix contacts and acquire a migratory, invasive phenotype. Thus modulation of cell-cell and cell-matrix adhesive events likely plays a critical role in tissue remodeling during tumor progression. Subsequent alterations in cellular architecture mediated by modified extracellular matrix (ECM) attachments induce expression of proteinases that degrade ECM proteins, facilitating migration through the modified tissue to establish metastatic foci and removing matrix constraints that normally limit proliferation. Current research centers on the functional interplay between cadherin based cell-cell junctions, integrin-mediated cell-matrix contacts, and regulation of serine and metallo-proteinases in two tumor model systems: epithelial ovarian carcinoma and squamous cell carcinoma of the oral cavity. Ongoing research utilizes an integrative approach involving examination of 2-dimensional (2D) and 3D organotypic tissue culture systems and ex vivo tissue analyses complemented by in vivo murine tumor models and investigation of human tumors. Understanding the molecular mechanisms by which tumor cells orchestrate multiple microenvironmental cues to regulate the expression and activity of metastasis-associated proteinases is the major focus of the laboratory.

Additional collaborative research with Matthew Ravosa (University of Notre Dame) focuses on the relationship between mechanical loading and tissue remodeling in the development and ageing of the masticatory apparatus.


Johnson, J.J.; Miller, D.L.; Jiang, R.; Liu, Y.; Shi, Z.; Tarwater, L.; Williams, R.; Balsara, R.; Sauter, E.R.; Stack, M.S. “Protease Activated Receptor-2 (PAR-2)-Mediated Nf-kB Activation Suppresses Inflammation-Associated Tumor Suppressor MicroRNAs in Oral Squamous Cell Carcinoma.” J. Biol. Chem. 2016, 291(13), 6936-6945.

Liu, Y.; Metzinger, M.; Lewellen, K.; Cripps, S.N.; Carey, K.D.; Harper, E.I.; Shi, Z.; Tarwater, L.; Grisoli, A.; Lee, E.; Slusarz, A.; Yang, J.; Loughran, E.A.; Conley, K.; Johnson, J.J.; Klymenko, Y.; Bruney, L.; Liang, Z.; Dovichi, N.J.; Cheatham, B.; Leevy, W.M.; Stack, M.S. “Obesity Contributes to Ovarian Cancer Metastatic Success Through Increased Lipogenesis, Enhanced Vascularity, and Decreased Infiltration of M1 Macrophages.” Cancer Res. 2015, 75, 5046-5057.

Burkhalter, R.J.; Westfall, S.D.; Liu, Y.; and Stack, M.S. “Lysophosphatidic Acid Initiates Epithelial to Mesenchymal Transition and Induces beta-Catenin-Mediated Transcription in Epithelial Ovarian Carcinoma.” J. Biol. Chem. 2015, 290, 22143-22154.

Miller, D.L.; Davis, J.W.; Taylor, K.H.; Johnson, J.; Shi, Z.G.; Williams, R.; Atasoy, U.; Lewis, J.S.; Stack, M.S. “Identification of a Human Papillomavirus-Associated Oncogenic miRNA Panel in Human Oropharyngeal Squamous Cell Carcinoma Validated by Bioinformatics Analysis of The Cancer Genome Atlas.” Am. J. Pathol. 2015, 185 (3), 679-692.

Bruney, L.; Conley, K.C.; Moss, N.M.; Liu, Y.Y.; Stack, M.S. “Membrane-type I matrix metalloproteinase-dependent ectodomain shedding of mucin16/CA-125 on ovarian cancer cells modulates adhesion and invasion of peritoneal mesothelium.” Biol. Chem. 2014, 395 (10), 1221-1231.

ROBERT V. STAHELINAdjunct Associate Professor(574) 631-5054 [email protected]

Postdoctoral research associate, University of Illinois at Chicago, 2003–05

PhD, Chemistry, University of Illinois at Chicago, 2003BS, Biochemistry, University of Illinois at Chicago, 1998

Medicinal Chemistry

A large number of cytoplasmic proteins involved in cell signaling and membrane trafficking reversibly translocate to different cellular membranes in response to specific stimuli. Many of these peripheral proteins contain one or more modular domains specialized in lipid binding. The Stahelin laboratory’s work aims to progress our understanding of the mechanisms by which reversible binding of lipid binding domains and their host proteins to different cell membranes is mediated and regulated, with an emphasis on how kinetics and energetics of their membrane-protein interactions are modulated by different factors. The long-term objective of this research is to apply principles learned from biochemical and biophysical studies to the generation of novel therapeutics to combat cancer, arthritis, asthma, and infectious diseases such as Ebola and HIV.

Research Projects

1) Evaluation of the replication cycle, including budding and egress of tropical viruses such as Ebola.

2) Investigation of the differential mechanisms of activation of cPLA2 isoform,s an important step toward the elucidation of the pathogenesis of inflammatory diseases.

3) Elucidation of the membrane-targeting mechanisms of human Nedd4 proteins and their mechanism of ubiquitin transfer to substrate.

4) Development of fluorescent sensors for biological activity and lipid mapping of enzymes in live cells and in vivo.


Johnson, K.A.; Taghon, G.J.; Scott, J.L.; Stahelin, R.V. “The Ebola Virus matrix protein, VP40, requires phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) for extensive oligomerization at the plasma membrane and viral egress.” Sci. Rep. 2016, 6, 19125.

Wijesinghe, K.J.; Stahelin, R.V. “Investigation of the Lipid Binding Properties of the Marburg Virus Matrix Protein VP40.” J. Virol. 2016, 90, 3074-3085.

Del Vecchio, K.; Stahelin, R.V. “Using Surface Plasmon Resonance to Quantitatively Assess Lipid-Protein Interactions.” Methods Mol. Biol. 2016, 1376, 141-153.

Adu-Gyamfi, E.; Johnson, K.A.; Fraser, M.E.; Scott, J.L.; Soni, S.P.; Jones, K.R.; Digman, M.A.; Gratton, E.; Tessier, C.R.; Stahelin, R.V. “Host Cell Plasma Membrance Phosphatidylserine Regulates the Assembly of Budding Ebola Virus.” J. Virol. 2015, 89, 9440-9453.

Soni, S.P.; Stahelin, R.V. “The Ebola virus matrix protein VP40 selectively induces vesiculation from phosphatidylserine-enriched membranes.” J. Biol. Chem. 2014, 289, 33590-33597.

Stahelin, R.V. “Membrane binding and bending in Ebola VP40 assembly and egress.” Front. Microbiol. 2014, 5, 300.

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RICHARD E. TAYLORProfessor

Interim Director, Warren Family Research Center for Drug Discovery and Development


Postdoctoral research associate, Stanford University, 1992–95PhD, Organic Chemistry, Rensselaer Polytechnic Institute,

1992BS, Chemistry, State University of New York at Oswego,

1987

Synthetic Organic Chemistry

The Taylor group has investigated a number of complex polyketide natural products, with unique or unknown modes of action. The Taylor group’s expertise in the area of synthesis, conformational analysis, and polyketide biosynthesis has placed them in a unique position to fully exploit these lead structures’ potential as therapeutic agents. In the last several years they have completed the total synthesis of the epothilones A, B, C, and D; myriaporones 1, 3, and 4;, the marine polyketide, peloruside A, and most recently, the myxobacterium-derived, gephyronic acid. In addition, they have prepared modified versions of these compounds— analogues—to learn more about the importance of key structural features with unique perspective focused on the determination of the bound conformation. Through detailed NMR and computational studies of the natural product and several designed analogues, the group seeks to identify the conformation required for biological activity. In the past related studies of the epothilones has identified the bound conformation and several unique analogues that were subsequently patented and licensed to the pharmaceutical industry for further development. More recently, these same compounds have shown promise as potential leads for the treatment of Alzheimer’s disease. The group has demonstrated that the information gained from what they have termed conformation-activity relationships complements classic SAR with the goal of providing a detailed pharmacophore model and assisting in the design of future chemotherapeutic agents.

Another unique aspect of their analogue design strategy is the exploitation of biosynthetic enzymes called polyketide synthases. Through characterization and exploitation of bacterial genes encoding for the production of natural products they seek to create engineered organisms with the ability to generate large quantities of biologically active natural products and medicinally relevant analogues capable of alleviating any concerns about the high cost of total synthesis of compounds of this complexity.

Awards

Fellow of the American Association for the Advancement of Science (AAAS), 2009

Rev. Edmund P. Joyce, C.S.C., Award for Excellence in Undergraduate Teaching, 2007

Eli Lilly Grantee Award, 2000

John A. Kaneb Teaching Award, 2002National Science Foundation’s Faculty Early Career Award,

1998


Wagner, D.T.; Stevens, D.C.; Mehaffey, M.R.; Manion, H.R.; Taylor, R.E.; Brodbelt, J.S.; Keatinge-Clay, A.T. “alpha-Methylation follows condensation in the gephyronic acid modular polyketide synthase.” Chem. Commun.2016, 52(57), 8822-8825.

Chang, C.F.; Stefan, E.; Taylor, R.E. “Total Synthesis and Structural Reassignment of Lyngbyaloside C Highlighted by Intermolecular Ketene Esterification.” Chem. Eur. J. 2016, 21(30), 10681-10686.

Stefan, E.; Taylor, R.E. “1,5-Hydride Transfer Protocol for the Synthesis of beta-Branched Polyketide Structural Units.” Tetrahedron Lett. 2015, 56 (23), 3416-3419.

Naini, A.; Muthukumar, Y.; Raja, A.; Franke, R.; Harrier, I.; Smith, A.B.; Lee, D.; Taylor, R.E.; Sasse, F.; Kalesse, M. “The Synthesis and Biological Evaluation of Desepoxyisotedanolide and a Comparison with Desepoxytedanolide.” Angew. Chem. Int. Ed. 2015, 54(23), 6935-6939.

Larsen, E.M.; Wilson, M.R.; Taylor, R.E. “Conformation-activity relationships of polyketide natural products.” Nat. Prod. Rep. 2015, 32(8), 1183-1206.

Young, J.; Stevens, D.C.; Carmichael, R.; Tan, J.; Rachid, S.; Boddy, C.N.; Muller, R.; Taylor, R.E. “Elucidation of Gephyronic Acid Biosynthetic Pathway Revealed Unexpected SAM-Dependent Methylations.” J. Nat. Prod.2013, 76(12), 2269-2276.

AARON TIMPERMANConcurrent ProfessorDirector of Research, Advanced Diagnostics and Therapeutics(574) 631-7868

[email protected]

PhD, Analytical Chemistry, University of Illinois, 1995BS, Chemistry, Saint Louis University, 1990

Microfluidic and Proteomic Technology Development

Our group develops novel microfluidic and proteomic technologies to address problems in counter-terrorism and medicine. Thus, we work at the intersection of chemistry and biology, and are engaged with collaborators in a number of fields, including biology, engineering, physics, and medicine. More specifically, our studies focus on: (a) the detection of pathogenic bacteria and viruses, (b) the study of cell surface receptors, (c) the bacterial stress response, and (d) the development of microfluidic systems for combined bottom-up and top down proteomics. In addition to our more applied work, we often encounter phenomena that have not been fully characterized and lead to new lines of basic research. Examples of basic research topics include ion concentration polarization in nanofluidic/microfluidic interfaces and particle acceleration in electrophoresis.

Microfluidic Systems for the Detection of Pathogens and Investigation of Cell Surface Receptors. We are developing a novel microfluidic electrophoresis that is generally applicable to the analysis of particles, namely cells and viruses. For pathogen detection, this system integrates a selective binding assay and physical characterization of the bound particle to effectively eliminate false positives and detect aggregates. For biomedical studies, we will use labeled probes to interrogate cell surface receptors in-situ (i.e., in their native environment). In contrast, surface plasmon resonance requires removal of the receptors and immobilization on a solid support.

Proteomics of the Bacterial Stress Response. Bacteria encounter many stressors in the environment and must respond to these stressors to improve their survival. Because a cell’s functional machinery is composed of proteins, stress responses invariably cause numerous changes in levels of proteins within a cell. Additionally, proteins can be directly modified by chemical or physical insults. Our investigation is focused on a critical question – can the effects of a single stressor be distinguished from the numerous other environmental stressors that bacteria may encounter? The particular stressor that we are studying is the ionizing radiation that would be emitted from a dirty bomb or nuclear weapon. Additionally, we are investigating environmental effects on the stress response to antibiotics in bacteria.

Microfluidic Devices for Combined Top-Down and Bottom-Up Proteomics. Proteomics, the determination of all the proteins in an organism in a specific state, is a challenging endeavor. Whereas top-down (whole protein analysis) and bottom-up proteomics (peptide level analysis) are highly complimentary, these two methods are yet to be combined post-separation. To combine these two approaches, we are utilizing the nanoliter fractionation capabilities for microfluidic devices, along with our nanofluidic/microfluidic interface (NMI) concentrators to provide revolutionary capabilities for the post-separation analysis of intact proteins and peptides from the same protein.


Wang,H.; Nandigana, V.R.R.; Jo, K.D.; Aluru, N.R.; Timperman, A.T. “Controlling the ionic current rectification factor of a nanofluidic/microfluidic interface with symmetric nanocapillary interconnects.” Anal. Chem. 2015, 87, 3598-3605.

Grimme, J.; King, T.; Jo, K.D.; Cropek, D.; Timperman, A.T. “Development of fieldable lab-on-a-chip systems for detection of a broad array of targets from toxicants to biowarfare agents.” J. Nanotech. Eng. Med. 2013, 4, 020904-1 - 020904-8.

Jo, K.D.; Schiffbauer, J.E.; Edwards, B.E.; Carroll, R.L.; Timperman, A.T. “Fabrication and performance of a microfluidic traveling-wave electrophoresis system.” Analyst 2012, 137, 875-883.

Reschke, B.R.; Timperman, A.T. “A study of electrospray ionization emitters with differing geometries with respect to flow rate and electrospray voltage.” J. Am. Soc. Mass Spectr. 2011, 22, 2115-2124.

Mao, X.; Reschke, B.R.; Timperman, A.T. “Analyte transport past a nanofluidic intermediate electrode junction in a microfluidic device.” Electrophoresis 2010, 31, 2686-2694.

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EMILY Y. TSUIAssistant Professor


Postdoctoral Fellow, University of Washington, 2014-2017PhD, Chemistry, California Institute of Technology, 2014BS, Chemistry, Massachusetts Institute of Technology, 2008

Design and Synthesis of Artificial Catalytic Systems

Research in the Tsui group will focus on the development of new catalysts using principles and techniques from the areas of bioinorganic, organometallic, and nanomaterials chemistry. Biological enzymes and heterogeneous catalysts are capable of activating very strong bonds in small molecules with high activity and specificity. We will design transition metal complexes and nanoscale materials as models of these systems, incorporating new structural or compositional motifs from enzymatic or heterogeneous active sites to enhance the performance of our artificial catalytic systems. An improved fundamental understanding of these systems will have important applications in chemical synthesis, liquid fuels production, and energy storage.


Tsui, E.Y.; Kanady, J.S.; Agapie, T. “Synthetic Cluster Models of Biological and Heterogeneous Manganese Catalysts for O2 Evolution.” Inorg. Chem. 2013, 52, 13833-13848.

Tsui, E.Y.; Agapie, T. “Reduction Potential of Heterometallic Manganese-Oxido Cubane Complexes Modulated by Redox-Inactive Metals.” Proc. Natl. Acad. Sci. USA 2013, 110, 10084-10088.

Tsui, E.Y.; Tran, R.; Yano, J.; Agapie, T. “Redox-inactive Metals Modulate the Reduction Potential in Heterometallic Manganese-Oxido Clusters.” Nat. Chem. 2013, 5, 293-299.

Kanady, J.S.; Tsui, E.Y.: Day, M.W.; Agapie, T. “A Synthetic Model of the Mn3Ca Subsite of the Oxygen-Evolving Complex in Photosystem II.” Science 2011, 333, 733-736.

Tsui, E.Y.; Day, M.W.; Agapie, T. “Trinucleating Copper: Synthesis and Magnetostructural Characterization of Complexes Supported by a Hexapyridyl 1,3,5-Triarylbenzene Ligand.” Angew. Chem. Int. Ed. 2011, 50, 1668-1672.

Tsui, E.Y.; Muller, P.; Sadighi, J.P. “Reactions of a Stable Monomeric Gold(I) Hydride Complex.” Angew. Chem. Int. Ed. 2008, 47, 8937-8940.

SERGEI B. VAKULENKOResearch Professor(574) [email protected]

DSc, Biology, National Research Center of Antibiotics, Moscow, 1991

PhD, National Research Center of Antibiotics, Moscow, 1981

MD, School of Medicine, St. Petersburg, 1976

Biochemical and Molecular Mechanisms of Antibiotic Resistance in Bacteria

Antibiotics have revolutionized the treatment of infectious diseases, saving countless human lives. Selection and dissemination of antibiotic-resistant microorganisms pose a serious threat for the current and future utility of these drugs. Research in the Vakulenko group focuses on bacterial enzymes responsible for resistance to two major classes of antimicrobial agents: β-lactams and aminoglycosides. Bacteriology, molecular biology, enzyme kinetics and x-ray crystallography are used to elucidate the structural and kinetic mechanisms of resistance to these antibiotics and to study the evolution of β-lactamases and aminoglycoside-modifying enzymes towards the expansion of their substrate profiles and increased catalytic efficiency.


Toth, M.; Antunes, N.T.; Stewart, N.K.; Frase, H.; Bhattacharya, M.; Smith, C.A.; Vakulenko, S.B. “Class D ß-lactamses do exist in Gram-positive bacteria.” Nat. Chem. Biol. 2016, 12, 9-14.

Smith, C.A.; Antunes, N.T.; Stewart, N.K.; Frase, H.; Toth, M.; Kantardjieff, K.A.; Vakulenko, S.B. “Structural basis for enhancement of carbapenemase activity in the OXA-51 family of class D ß-lactamases.” ACS Chem. Biol. 2015, 10, 1791-1796.

Stewart, N.K.; Smith, C.A.; Frase, H.; Black, D.J.; Vakulenko, S.B. “Kinetic and structural requirements for carbapenemase activity in GES-type ß-lactamases.” Biochemistry 2015, 54, 588-597.

Smith, C.A.; Toth, M.; Wiess, T.M.; Frase, H.; Vakulenko, S.B. “Structure of the bifunctional aminoglycoside-resistance enzyme AAC(6’)-le-APH(2’’)-la revealed by crystallographic and small-angle X-ray scattering analysis.” Acta Crystallogr. D 2014, 70, 2754-2764.

Smith, C.A.; Antunes, N.T.; Stewart, N.K.; Toth, M.; Kumarasiri, M.; Chang, M.; Mobashery, S.; Vakulenko, S.B. “Structural basis for carbapenemase activity of the OXA-23 ß-lactamase from Acinetobacter baumannii.” Chem. and Biol. 2013, 20, 1107-1115.

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OLAF WIESTProfessor


Dr. rer. nat. (PhD), Organic Chemistry, University of Bonn, Germany 1993

Diploma (MS), Organic Chemistry, University of Bonn, Germany, 1991

Computational and Organic Chemistry Computer-Aided Molecular Design

The central topic of the research in the Wiest group is how molecules interact and react. The structure and energetics of non-covalent complexes and transition states is probed theoretically and experimentally.

The detailed understanding of intermolecular interactions can then be exploited for the design of assays for biophysical studies and for drug design. Four distinct areas of research are currently under investigation: (1) development of epigenetic modulators targeting histone deacetylases and bromodomains as chemical tools and drug leads (2) rare and neglected diseases, specifically Niemann Pick Type C disease (3) mechanistic studies of transition metal and enzyme catalyzed reactions and (4) development of Q2MM methods for the virtual screening of chiral ligands for asymmetric catalysis.

The research in the Wiest group uses a wide range of experimental and computational methods that are applied to fundamental and applied problems in organic and biophysical chemistry. In this work, we collaborate with a number of other researchers in synthetic chemistry, biology, physics, and at medical schools at Notre Dame and around the world.

Awards

Kaneb Teaching Award, 2004Camille Dreyfus Scholar, 2001NSF CAREER Award, 1997FIRST Award, National Institutes of Health, 1997Feodor Lynen Fellow of the Alexander von Humboldt

Foundation, University of California at Los Angeles, 1993–95


Xu, W.; Arieno, M.; Löw, H.; Huang, K.; Xie, X.; Crutcher, T.; Ma, Q.; Xi, J.; Huang, B.; Wiest, O.; Hong, L.; Meggers, E. “Metal-Templated Design: Enantioselective Hydrogen-Bond-Driven Catalysis Requiring Only Parts-per-million Catalyst Loading.” J. Am. Chem. Soc. 2016, 138, 8774-8780.

Lee, J.M.; Zhang, X.; Wu, Y.D.; Norrby, P.O.; Helquist, P.; Wiest, O. “Stereoselectivity in (Acylox)borane-Catalyzed Mukaiyama Aldol Reactions.” J. Org. Chem. 2016, 81, 5314-5321.

Hansen, E.; Rosales, A.R.; Tutkowski, B.M.; Norrby, P.O.; Wiest, O. “Prediction of Stereochemistry using Q2MM.” Acc. Chem. Res. 2016, 49, 996-1005.

Grigalunas, M.; Anker, T.; Norrby, P.O.; Wiest, O.; Helquist, P. “Ni-Catalyzed Alkenylation of Ketone Enolates Under Mild Conditions: Catalyst Identification and Optimization.” J. Am. Chem. Soc. 2015, 137, 7019-7022.

Mbengue, A.; Bhattacharjee, S.; Pandharkar, T.; Liu, H.N.; Estiu, G.; Stahelin, R.V.; Rizk, S.S.; Njimoh, D.L.; Ryan, Y.; Chotivanich, K.; Nguon, C.; Ghorbal, M.; Lopez-Rubio, J.J.; Pfrender, M.; Emrich, S.; Mohandas, N.; Dondorp, A.M.; Wiest, O.; Haldar, K. “A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria.” Nature 2015, 520 (7549), 683-U246.

Chen, K.; Zhang, X.X.; Wu, Y.D.; Wiest, O. “Inhibition and Mechanism of HDAC8 Revisited.” J. Am. Chem. Soc. 2014, 136 (33), 11636-11643.

McCourtney Hall

Completed in 2016, McCourtney Hall is a world-class research facility with more than 220,000 square feet, including 100,000 square feet of open laboratory and team space for cutting-edge, collaborative research in the colleges of science and engineering.

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