String Method
Conformational transitions underlie a vast array of biological processes (e.g. enzyme catalysis, DNA replication, refolding of misfolded proteins, ATP synthesis, transport by molecular motors, muscle contraction, multidrug resistance), but are extremely difficult to investigate by experimental methods because of the small spatiotemporal scales involved. Computer simulation of conformational transitions in biomolecules is a generally unsolved problem in computational science because spontaneous transitions in proteins often require millisecond simulation times. Many macromolecular processes therefore remain well beyond the reach of conventional molecular dynamics simulations, which are currently limited to nano- to micro-second simulation lengths.To overcome the time-scale limitation of standard MD simulations, various enhanced techniques have been developed. However, most of the methods require a priori information, e.g. specification of a "reaction coordinate" or coarse-grained system variables, which are generally unknown, except for simple molecular systems. We have extended the 'string method' originally introduced by W.E and coworkers beyond proof-of-principle biological models to transitions in proteins of biological importance, such as Myosin VI and Calmodulin.As a member of the Karplus group, I have developed fully parallel string code via MPI, recently interfaced with the CHARMM molecular dynamics program, in which a large number of weakly interacting copies of a single system are treated simultaneously using hundreds to thousands of CPU cores. Details on how to obtain the source code are provided here.
References:
1)W. E, W. Ren, and E. Vanden-Eijnden, J. Chem. Phys. 126, 164103 (2007).
2)V. Ovchinnikov, E. Vanden-Eijnden, and M. Karplus. Investigations of alpha-helix <--> beta-sheet transition pathways in a miniprotein using the finite-temperature string method. J. Chem. Phys., 140:175103, 2014. (preprint)
3)V. Ovchinnikov and M. Karplus. Analysis and elimination of a bias in targeted molecular dynamics simulations
of conformational transitions: Application to Calmodulin. J. Phys. Chem. B, 116:8584–8603, 2012. (preprint)
4)V. Ovchinnikov, M. Karplus, and E. Vanden-Eijnden. Free energy of conformational transition paths in
biomolecules: The string method and its application to myosin VI. J. Chem. Phys., 134:085103, 2011. (preprint)
5)V. Ovchinnikov, M. Cecchini, E. Vanden-Eijnden, and M. Karplus. A conformational transition in the myosin VI converter contributes to the variable step size. Biophys. J., 101:2436–2444, 2011. (preprint)
