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How mechanical force regulates the function of proteins?
Vesa Hytönen ([email protected])
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!
