Mechanochemical Coupling in Myosin:  A Theoretical Analysis with Molecular Dynamics and Combined QM/MM Reaction Path Calculations

To elucidate the detailed mechanism of ATP hydrolysis in myosin, molecular dynamics employing classical force field and reaction path analyses employing a combined quantum mechanical and molecular mechanical (QM/MM) potential were carried out. Although the QM/MM reaction path analyses have limited accuracy due to the lack of extensive conformational sampling, the present work showed that sensible energetics much closer to experimental measurements than previous computational studies can be obtained once the protein environment is included. In the two associative mechanisms studied here, the pathway that involves the conserved residue, Ser 236, as the proton relay group was found to have a lower rate-limiting barrier. However, it was also shown that if O2γ gets protonated, the mechanism without invoking any proton relay has only a slightly higher barrier and therefore may also contribute, especially in mutants such as Ser 236A. By performing calculations for two different motor domain conformations, it was...