Myosin V executes steps of variable length via structurally constrained diffusion

Myosin V is a molecular motor that performs intracellular transport by moving along actin filaments and generating energy through ATP hydrolysis. By alternating head detachment, myosin V steps hand-over-hand with the free head executing a random diffusive search for actin binding sites. Recent experiments suggest that the joint between the myosin lever-arms is not freely rotating, as indicated by previous studies, but instead has a preferred angle giving rise to structurally constrained diffusion. We address this controversy by developing a comprehensive model of myosin V, combining a polymeric description of the diffusive search with the kinetic network of states occupied during the stepping cycle. When the joint is constrained, our model predicts diffusion similar to that recently observed, allowing us to estimate bounds on the constraint energy. We also analyze the consistency of constrained diffusion with previous measurements of step distributions and the load dependence of the forward-to-backward step ratio, run length, and velocity, finding good agreement for each. The theory lets us address the biological significance of the constrained joint and provides testable predictions of new myosin behaviors, including a stomp distribution and the run length under off-axis force.