LAUSR

Significance Interactions between myosin and actin are essential in producing various cellular forces. Targeting cardiac myosin, several small molecules have been developed to treat cardiomyopathy. A clear mechanistic picture of the allosteric control in the actomyosin complex can potentially facilitate drug design by uncovering functionally important intermediate states. Here, integrating Rosetta comparative modeling and accelerated molecular dynamics, we reveal how ATP-hydrolysis product release correlates with myosin powerstroke and tight binding to actin. The predicted metastable states and corresponding energetics complement available experimental data and provide insights into the timing of elementary mechanochemical events. Our method establishes a framework to characterize at an atomistic level how a molecular motor translocates along a filament.