amber parameters for pseudouridine delon wilson advisor: j. santalucia
TRANSCRIPT
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AMBER Parameters for Pseudouridine
Delon WilsonAdvisor: J. SantaLucia
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Outline
Introduction and MotivationPseudouridine & Modified Nucleic AcidsAtomic charge in MM
RESP/ MethodThe MEPCharge Fitting with Restraints
Results Conclusion
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Nucleic Acid Structure
Base
Sugar
PhosphateG,C,A,T (DNA)
G,C,A,U (RNA)
Deoxyribose (DNA)Ribose (RNA)
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PSU and Modified NA’s
Found as natural substances or obtained synthetically
Pseudouridine – 1% in rRNA, tRNA
produced by chemically modifiying one of the four bases (G, C, A, and T in DNA or U in RNA)
Important in biochemical regulation
Used extensively in chemistry, biochemistry, and pharmacology as probes to study biological mechanisms
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PSU and Modified NA’s
Major cause of spontaneous mutation in E. coli results from the presence of an unusual base in the DNA.
e.g. 5-MethylCytosine
Successful applications as antibiotics or chemotherapeutic agents
e.g. AZT interferes with the replication of HIV (Human Immunodeficiency Virus)
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Molecular Mechanics
Modeling of biological systems
Accurate representation of electrostatic interactions
crucial for force field application
Suitable force field parameters required for molecular
mechanics and dynamics
force constants, atom types, bond distances, atomic
charges
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Molecular Mechanics
Amber: A suited of programs developed by Peter
Kollman & Coworkers at UCSF
Force field referred to by same name
Parameters for regular NA’s (A,C,T,G,U) developed
Suitable parameters for modified NA’s not available
An albatross to computations for systems involving
substantial amounts of mod. NA’s
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Potential Energy ModelThe force field energy
where
ticelectrostavdwtorsionbendstrFF EEEEEE
2eqbonds
rstr rrKE 2
angleseqbend KE
nK
En
ntorsion cos1
2
ji ij
ij
ij
ijvdw R
B
R
AE
612
ji ij
jiticelectrosta R
qqE
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Pseudouridine
Base joined to ribose via C-C,Vs. C-N in regular NA’s
Uridine
Psu
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Starting structure from PDB
Perform Geometry Optimization (HF-631G*)
ComputeElectrostatic Potential Charges
(pop=mk)
Fit ESP charges(RESP)
MD simulation (AMBER)
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Initial Structure
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Gaussian Keywords
#p hf 6/31-g(d) opt pop=mk
geom=connectivity test iop(6/33=2)
Duration: around 5hrs
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ESP: Some Common Methods
Mulliken Population Analysis-does not
reproduce ESP closely enough
Natural Population Analysis`
ESP derived using CHelpG scheme
ESP derived using MKS scheme
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Calculation of ESP/MEP
10 14i
i i
Q
r
Calculate approximate Ψ from eq geom
Calculate e density from psi
The ESP at point 1 is:
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RESP
Least squares algorithm derives atom centered
charges that best reproduces MEP
Potential calculated on large number of points
on 4 shells of surfaces defined by {1.4, 1.6, 1.8,
2.0} x VDW radii
ESP at each point derived from QM
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Results .4312(.4295)
-.6135(-.6223)
.0748(.0679)
.0748(.0679)
.0264(.0558)
.0788(.1065)
.1171(.1174)
-.3604(-.3548)
.0461(.0615)
.2808(.2022) .0736
(.0670)
.0974(.0972) -.5962
(-.6139)
.4098(.4186)
.3885(.4376)
-.6271(-.6541)
.0303(-.1081)
.1714(.2405)
-.5332(-.6230)
.3842(.8922)
.0069(-.5317)
-.0759(.3896)
.2104(.1226)
.5173(.9290)
-.5841(-.6096)
-.3407(-.6770)
.3418(.4311)
-.2671(-.7255)
.3402(.3859)
Partial charges on pseudouridine: values in parenthesis from Amber website, std=0.23
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Results Calculations performed on a single Pentium IV
processor.
Average CPU time to perform the geometry optimization of each nucleoside in the order of several hours (~5)
Charges for each ribonucleotide are in a good
agreement with AMBER standard reference file (all_nuc94.in).
Calculations on pseudouridine deviate more than expected from the contributed values provided at the AMBER website.
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…To do
Investigate the dependence of the charges on conformation
Determine force field parameters for all (~103) of the naturally occurring modified nucleotides that occur in RNA and DNA.
Extend the AMBER force field so that nuclei acids with modifications may be routinely modeled.
Develop a novel force field specifically tailored to nucleic acid applications (NA_FF).
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References/Acknowlegment
U. C. Singh and P. A. Kollman
J. Comp. Chem. vol.5, no.2, 129-145 (1984)
B.H. Besler, K.M. Merz Jr., and P.A. Kollman
J. Comp. Chem. vol.11, no.4, 431-439(1990)
JSL Lab
Schlegel Lab
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Questions etc…
Thank you