On the\nControl of Directionality of Myosin

The origin of the unique directionality\nof myosin has been a problem\nof fundamental and practical importance. This work establishes in\na conclusive way that the directionality is controlled by tuning the\nbarrier for the rate-determining step, namely, the ADP release step.\nThis conclusion is based on exploring the molecular origin behind\nthe reverse directionality of myosins V and VI and the determination\nof the origin of the change in the barriers of the ADP release for\nthe forward and backward motions. Our investigation is performed by\ncombining different simulation methods such as steer molecular dynamics\n(SMD), umbrella sampling, renormalization method, and automated path\nsearching method. It is found that in the case of myosin V, the ADP\nrelease from the postrigor (trailing head) state overcomes a lower\nbarrier than the prepowerstroke (leading head) state, which is also\nevident from experimental observation. In the case of myosin VI, we\nnoticed a different trend when compared to myosin V. Since the directionality\nof myosins V and VI follows a reverse trend, we conclude that such\ndifferences in the directionality are controlled by the free energy\nbarrier for the ADP release. Overall, the proof that the directionality\nof myosin is determined by the activation barrier of the rate-determining\nstep in the cycle, rather than by some unspecified dynamical effects,\nhas general importance.