Human Cardiac β-myosin Powerstroke Energetics: Thin Filament, Pi Displacement, and Mutation Effects

Overview

Journal Biophys J

Publisher Cell Press

Specialty Biophysics

Date 2024 Jul 13

PMID 39001604

Authors

Bai Hei

Jil C Tardiff

Steven D Schwartz

Affiliations

Soon will be listed here.

Abstract

The powerstroke of human cardiac β-myosin is an important stage of the cross-bridge cycle that generates force for muscle contraction. However, the starting structure of this process has never been resolved, and the relative timing of the powerstroke and inorganic phosphate (Pi) release is still controversial. In this study, we generated an atomistic model of myosin on the thin filament and utilized metadynamics simulations to predict the absent starting structure of the powerstroke. We demonstrated that the displacement of Pi from the active site during the powerstroke is likely necessary, reducing the energy barrier of the conformation change. The effects of the presence of the thin filament, the hypertrophic cardiomyopathy mutation R712L, and the binding of mavacamten on the powerstroke process were also investigated.

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