Computational Study of the Effect of Point Mutations Perturbing the Recovery Stroke of Human Cardiac Beta-Myosin using Metadynamics

Abstract

Human cardiac myosin regulates the contractile performance of cardiac muscle by undergoing a sequence of steps, termed the cross-bridge cycle.The recovery stroke step being central to the contractile function, induces conformational changes which position the catalytic residues of myosin to catalyze ATP hydrolysis and hence is of particular interest. Though there have been experimental studies on Dictyostelium myosin II showing that perturbations in the recovery stroke by mutations can also affect its catalytic activity, but little has been known about the human cardiac myosin, especially, at the molecular level. In this study using computational methods, we aim to investigate in the same level of detail the process human cardiac β-myosin in both the wildtype and with mutations known to cause inherited cardiomyopathies. We have developed a model replicating the recovery stroke in human cardiac β-myosin by sampling the transition from the post-rigor state to the pre-powerstroke-ATP bound state using Metadynamics. Wildtype, R453C, I457T and I467T simulations were performed to detect any differences in the predicted free-energy changes. We expect that our results would predict a similar trend as that of the experimental studies on the ATPase activity of the human cardiac β-myosin in case of HCM causing mutations R453C and I457T and hence, may motivate us to extend this approach to other transitions involved in the mechanochemical cycle. This will help present a complete computational picture of the effect of genetic cardiomyopathies on human cardiac myosin.