Electrostatic Basis of the Unidirectional Walking Motion in Myosin Molecular Motors

Abstract

Understanding the basis for the unidirectional motion of myosin motors on actin filaments require a quantitative energy based description of the overall functional cycle. Several experimental and theoretical studies have provided interesting insights on the functional cycle, but an understanding of the motor's unidirectionality from a non-phenomenological structure based free energy landscape is still missing. Here we use a coarse grained model of myosin V and generate a structure-based free energy surface of the largest conformational change, namely the transition from the post- to pre-power stroke movement. We also couple the observed energetics of ligand binding/hydrolysis and product release to that of the conformational surface to reproduce the energetics of the complete mechano-chemical cycle. It is found that the release in electrostatic free energy upon changing the conformation of the lever arm and the convertor domain from its post- to pre-power stroke states provides the necessary energy to bias the system towards the unidirectional movement of myosin V on actin filament. The free energy change of 11 kcal is also in the range of approximately 2-3 pN, which is consistent with the experimentally observed stalling force required to stop the motor completely on its track. The conformational-chemical coupling generating a successful power stroke cycle is believed to be conserved among most members of the myosin family, thus highlighting the importance of the previously unknown role of electrostatics free energy in guiding the functional cycle in other actin-based myosin motors.