Mutation-induced free-energy remodeling of recovery stroke and ATP hydrolysis in human cardiac β-myosin
Abstract
Human cardiac muscle function is regulated by interactions between the thick (myosin) and thin (actin) filaments, driven by conformational changes in myosin coupled to ATP hydrolysis, enabling force generation. During the recovery stroke, myosin undergoes conformational rearrangements that position active site residues for ATP hydrolysis and actin interaction, making it a critical step in the kinetic cycle. Genetic cardiomyopathy-causing mutations within myosin are known to affect ATPase activity of myosin, thereby altering force generation. Despite their established impact on myosin, the molecular mechanisms through which cardiomyopathy-causing mutations alter ATPase activity and force generation are yet to be elucidated. In this study, we investigate the modifications in the conformational properties and free-energy surface of two cardiomyopathy-causing cardiac β-myosin mutants, (Arg403Gln(R403Q)) and (Glu525Lys(E525K)). Additionally, we examine how these mutations affect the recovery stroke. We generate thermodynamically accurate and unbiased trajectories of native ATP hydrolysis using enhanced computational sampling methods. In agreement with the earlier study, our methodology successfully captured experimentally observed alterations in both the kinetic and equilibrium dynamics of the recovery stroke, and it delineated the pathway of ATP hydrolysis, including stabilization of the metaphosphate intermediate. Our calculations further demonstrated that a reduction in the…
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