Fig. 6.

A model for how force coordinates the kinetics of the myosin V head. Energy profile for a head bound to actin subjected to an external force. Under unloaded conditions (black curve) the transition between an intermediately bound state (AMD) to a strongly bound state (AM*D) is rapid and strongly biased to formation of the strongly bound state. After the myosin reaches this state, there is a rate-limiting transition where the motor releases ADP. If a motor experiences a forward force (green curve, mimicking a trailing head), the free energy is reduced as a function of the position along the reaction coordinate (28). The reaction remains limited by the final ADP release step, which is sped up very little because of a small change in the relative free energies between AM*D and the ADP release transition state. If the motor is working against a backward force (red curve, mimicking a leading head), the free energy increases as a function of reaction coordinate. The forward transition to AM*D becomes significantly slower and the reverse transition is favored compared with the release of ADP from the AM*D state. If the initial state is populated, the weakly bound myosin head might release from the actin because of an off-pathway dissociation of the AMD to A + MD (blue arrow). In a two-headed walking motor, the lead head experiences an increasing backward force as it tries to swing its lever arm because of the attachment to the stationary trailing head (black dashed line), locking the lead head in the initial AMD state.