Molecular Mechanism of Force Generation by the Actin-Myosin Complex During Cardiac Muscle Contraction

Abstract

Cardiac muscle contraction is performed by arrays of contractile proteins in the sarcomere. Serious heart diseases, such as cardiomyopathy, can often be results of mutations in myosin and actin, which slide along each other to generate force using the energy from ATP hydrolysis. All-atom molecular dynamics (MD) simulations have been growing its power in predicting protein structure-function relationships. However, such approaches are limited in the study of the myosin crossbridge cycle owing to the slow timescale as well as the lack of high-resolution structures of various intermediate states for the human cardiac myosin-actin complex. Here, combining comparative modeling and enhanced sampling MD simulations, we characterize how the myosin-actin interactions in human are influenced by the myosin functional states. By incorporating structural information from multiple templates, our comparative modeling provides conformational ensembles for different myosin-actin states, which enable us to efficiently sample the energy landscape using Gaussian accelerated MD simulations. Our results reveal novel interactions between key myosin loops and actin, which are consistent with recent cryo-EM density data. Furthermore, we find that the myosin cleft motion is impacted by the ATP binding site dynamics and that ADP release is coupled to the lever arm swing. Our approach demonstrates the potential to link genotype and molecular structures to the physical properties of the sarcomere.