How mechanical force regulates the function of proteins?

Vesa Hytönen (veshyto@mat.ethz.ch)

Research group of Professor Viola Vogel, Biologically Oriented Materials, Department of Materials, ETH-Hönggerberg, Zürich

Beowulf DayJanuary 30th, 2006

Folding of protein● Protein folding is

energetically favored reaction

● Components assisting folding could be needed (for example chaperones)

www.press.uillinois.edu Ferrera & Caflisch (2000), PNAS 97, 10780-

Conformation vs. function

● Different conformations of the protein can have different functions

● Native state vs. functional state

● Protein activation

Prion Biology and Diseases. Cold Spring Harbor Laboratory Press, NY, 1999.

Conformation vs. function● Different

conformations of the protein can have different functions

● Native state vs. functional state

● Protein activation

www.mad-cow.org

Brain tissues showing amyloid plaques caused by aggregation of the particularly

folded protein

Factors affecting protein conformation

● Physical parameters

– temperature, pressure etc.

● Chemical parameters

– pH, solvent electrophilicity etc.

● Mechanical forceMechanical force

– force applied via interactions

– force produced by the cell

Steered molecular dynamics

● Forced unfolding of protein

● NAMD molecular dynamics simulation

● 400 pN pulling force applied

Simulation methods ● Experimental protein structures used as a starting

material

● Protein solvated in explicit water and ions added to neutralize the system

● Periodic water box used

● Typical system contains ~100 000 atoms (~70-80% water)

● CHARMM27 force field used (Newtonian mechanics)

● NAMD simulation package (Developed by research group of Professor Klaus Schulten, www.ks.uiuc.edu)

● Visualization of simulations with VMD

Computation

● Simulation carried out in femtosecond resolution

● Typical simulation time is some nanoseconds

● To obtain 1 ns simulation of 100 000-atom system, ~24 hours simulation time is needed in Gonzales cluster using 64 processors

● Coordinates saved every ps -> 1 ns simulation produces about 2 GB of data.

● Atomic resolution of the protein and solvent behaviour

Conclusion

● Molecular dynamics simulations make it possible to study behaviour of proteins in equilibrium and non-equilibrium conditions

● We would like to study the role of mechanical signals in protein function regulation?

Computational research projects in the Professor Viola Vogel’s group

● Eileen Faucher – Functional properties of integrins

● John Saeger – Fluorescent proteins

● Lina Nilsson – Bacterial adhesion

● Vesa Hytönen – Dynamics of the focal contacts

Thank you!