BPS2026 – Probing Myomaker’s mechanism of action through molecular dynamics simulations

Muscle is composed of multi-nucleated cells, which are formed by the fusion of hundreds of mononucleated cells called myoblasts. Their fusion is then essential for muscle growth both in embryogenesis and in injury recovery. Myomaker is a transmembrane protein in muscle cells known to be both necessary and sufficient for myoblast fusion. However, its molecular mechanism of action remains unknown. The aim of our study is to provide insights into Myomaker function via a molecular dynamics approach. Together with our collaborator’s experimental observations of both wild-type and mutated Myomaker, we are able to identify the response of both the membrane and protein to mutations that affect protein activity. We also study the influence of the membrane environment by changing the lipid content of the simulations. Our first results show a significant membrane thinning, together with the formation of a water pocket around one of the target residues. Although the molecular mechanism of the contribution of Myomaker to fusion is unknown, the strong disruption of the membrane we observe suggests multiple paths to stress the membrane, as is necessary for fusion.