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Design principles governing the motility of myosin V

Significance Myosin V, a two-headed motor protein, ferries cellular cargo by walking hand-over-hand on actin filaments. Interplay between ATP-driven conformational changes in the heads and stress due to load produces a variety of stepping dynamics: The motor can step forward or backward, or “stomp,” where one head detaches and rebinds to the same site. We created an analytically solvable theory capturing all these behaviors, quantitatively matching a wide array of single-molecule experiments. We describe the structural and chemical design principles underlying the motor’s robust function, providing a guide for how bioengineering might alter its dynamics. The molecular motor myosin V (MyoV) exhibits a wide repertoire of pathways during the stepping process, which is intimately connected to its biological function. The best understood of these is the hand-over-hand stepping by a swinging lever arm movement toward the plus end of actin filaments. Single-molecule experiments have also shown that the motor “foot stomps,” with one hand detaching and rebinding to the same site, and back-steps under sufficient load. The complete taxonomy of MyoV’s load-dependent stepping pathways, and the extent to which these are constrained by motor structure and mechanochemistry, are not understood. Using a polymer model, we develop an analytical theory to describe the minimal physical properties that govern motor dynamics. We solve the first-passage problem of the head reaching the target-binding site, investigating the competing effects of backward load, strain in the leading head biasing the diffusion in the direction of the target, and the possibility of preferential binding to the forward site due to the recovery stroke. The theory reproduces a variety of experimental data, including the power stroke and slow diffusive search regimes in the mean trajectory of the detached head, and the force dependence of the forward-to-backward step ratio, run length, and velocity. We derive a stall force formula, determined by lever arm compliance and chemical cycle rates. By exploring the MyoV design space, we predict that it is a robust motor whose dynamical behavior is not compromised by reasonable perturbations to the reaction cycle and changes in the architecture of the lever arm.