BPS2026 – Altered dynamics in skeletal myosin with pathogenic missense mutations

Congenital myopathies are early-onset genetic disorders characterized by muscle weakness. A subclass, termed myosinopathies, is associated with mutations in various myosin isoforms. One of the most abundant myosin isoforms in skeletal muscle is fast type IIa myosin (MYH2). To date, nine missense mutations have been identified within the motor domain of MYH2. Following the discovery of Omecamtiv Mecarbil (OM), the first allosteric cardiac myosin activator, several myosin modulators have reached clinical trials. Although OM has not received FDA approval, it demonstrated the feasibility of selectively modulating cardiac myosin. Previous work from our group explained the molecular basis of OM’s selectivity for cardiac over skeletal myosin, while showing features that could be exploited to design skeletal-selective modulators. An open question remains whether pathogenic missense mutations alter MYH2 dynamics and how these changes propagate to the OM binding site. In this study, we found significant local and global dynamical differences in three pathogenic MYH2 missense mutants compared to wild-type myosin. Consistent with these findings, the OM binding pocket exhibited greater volume fluctuations in the mutants, and a hydrophilic subpocket was more accessible during the mutant simulations. These results provide new insights into mutant MYH2 dynamics and can be used to guide future in silico drug design.