How mechanical force regulates the function of proteins? Vesa Hytönen (veshyto@mat.ethz.ch)

1. 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 Day January 30th, 2006

2. 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-

3. 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.

4. Conformation vs. function • Different conformations of the protein can have different functions • Native state vs. functional state • Protein activation Brain tissues showing amyloid plaques caused by aggregation of the particularly folded protein www.mad-cow.org

5. Factors affecting protein conformation • Physical parameters • temperature, pressure etc. • Chemical parameters • pH, solvent electrophilicity etc. • Mechanical force • force applied via interactions • force produced by the cell

6. Steered molecular dynamics • Forced unfolding of protein • NAMD molecular dynamics simulation • 400 pN pulling force applied

7. 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

8. 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

9. 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?

10. 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

11. Thank you!