The mechanochemical coupling in the biomolecular motor myosin-II has been
analyzed with a combination of simulation methods including a coarse-grained
normal mode analysis, molecular dynamics simulations, free energy perturbation
and hybrid QM/MM calculations; these methods probed different aspects of the
mechanochemical coupling, and the results combined together have yielded new
insights into the working mechanism of myosin with atomic level of details.
Both hybrid QM/MM reaction path and classical free energy perturbation calcu-
lations indicated that the open-form of the motor domain is not capable of catalyzing
ATP hydrolysis, supporting the hypothesis from previous x-ray studies. Energetics
based analysis revealed that the activity of hydrolysis is regulated by several residues
in the Switch I and Switch II regions; in particular, the conserved salt-bridge between
Arg 238 and Glu 459 seems to have both direct influence through electrostatic inter-
actions and indirect effects by modulating the water structure in the active site.
Results from a coarse-grained normal mode analysis including atomic interactions
indicated that the large-scale conformational change involved in the Open-Closed
transition is highly correlated with the low-frequency normal modes of the motor
domain. A remaining question concerns the causal relationship between such elastic
type of motion and activities (salt-bridge formation, ATP hydrolysis) at the active site.
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