Exploring the effect of myosin modulators on the ATP hydrolysis step of human cardiac beta myosin using transition path sampling.

Abstract

In recent years, cardiac myosin emerged as a potent target for various therapeutic agents termed as myosin modulators in treating genetic cardiomyopathies. Omecamtiv Mecarbil (OM) is one such promising cardiac-specific drug directly binding to an allosteric site of the myosin motor domain. OM is observed to enhance cardiac contractions and affects the various stages of the cross-bridge cycle. Our study investigates the atomistic details of the variations caused by OM on the chemical reaction of ATP to ADP and HPO42- using the method of Transition Path Sampling. We also incorporated the study of mutant forms of myosin causing genetic cardiomyopathies: R712L, P710R and F764L in presence of OM to observe the mutation specific behavior of the same on the hydrolysis step. We also further extended our methodology to study the effect of the recently FDA approved myosin effector Mavacamten on the ATP hydrolysis step as well. Unlike OM, mavacamten is observed to inhibit cardiac contractile performance. Since the crystal structures of mavacamten-bound myosin are not available yet, we employed docking process to develop probable structure of the same. This study will help provide a detailed molecular level understanding of the effect of the two classes of the cardiac-specific myosin effectors on the hydrolysis step and hence, further expand the approach to the other significant steps of the chemomechanical cycle, aiding in targeted applications of the therapeutic agents.