TY - JOUR
T1 - Free energy of conformational transition paths in biomolecules
T2 - The string method and its application to myosin VI
AU - Ovchinnikov, Victor
AU - Karplus, Martin
AU - Vanden-Eijnden, Eric
N1 - Funding Information:
The authors are grateful to Giovanni Ciccotti, Maddalena Venturoli, and Kwangho Nam for stimulating discussions. Supercomputer resources for the calculations performed in this study were provided by the National Energy Resource Supercomputing Center and the FAS Research Computing Group at Harvard. V.O. acknowledges financial support under the NRSA fellowship 1F32GM083422-01. The work done at Harvard was supported in part by a grant from the National Institutes of Health and by a grant from the Human Frontiers Grant Science Program. E.V.-E. was supported by a grant from the National Science Foundation (Grant No. DMS-0708140) and by a grant from the Office of Naval Research (Grant No. N00114-04-1-6046).
PY - 2011/2/28
Y1 - 2011/2/28
N2 - A set of techniques developed under the umbrella of the string method is used in combination with all-atom molecular dynamics simulations to analyze the conformation change between the prepowerstroke (PPS) and rigor (R) structures of the converter domain of myosin VI. The challenges specific to the application of these techniques to such a large and complex biomolecule are addressed in detail. These challenges include (i) identifying a proper set of collective variables to apply the string method, (ii) finding a suitable initial string, (iii) obtaining converged profiles of the free energy along the transition path, (iv) validating and interpreting the free energy profiles, and (v) computing the mean first passage time of the transition. A detailed description of the PPS↔R transition in the converter domain of myosin VI is obtained, including the transition path, the free energy along the path, and the rates of interconversion. The methodology developed here is expected to be useful more generally in studies of conformational transitions in complex biomolecules.
AB - A set of techniques developed under the umbrella of the string method is used in combination with all-atom molecular dynamics simulations to analyze the conformation change between the prepowerstroke (PPS) and rigor (R) structures of the converter domain of myosin VI. The challenges specific to the application of these techniques to such a large and complex biomolecule are addressed in detail. These challenges include (i) identifying a proper set of collective variables to apply the string method, (ii) finding a suitable initial string, (iii) obtaining converged profiles of the free energy along the transition path, (iv) validating and interpreting the free energy profiles, and (v) computing the mean first passage time of the transition. A detailed description of the PPS↔R transition in the converter domain of myosin VI is obtained, including the transition path, the free energy along the path, and the rates of interconversion. The methodology developed here is expected to be useful more generally in studies of conformational transitions in complex biomolecules.
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U2 - 10.1063/1.3544209
DO - 10.1063/1.3544209
M3 - Article
C2 - 21361558
AN - SCOPUS:79952096187
SN - 0021-9606
VL - 134
JO - Journal of Chemical Physics
JF - Journal of Chemical Physics
IS - 8
M1 - 085103
ER -