Binding pocket dynamics along the recovery stroke of human β-cardiac myosin

PLoS Comput Biol. 2023 May 18;19(5):e1011099. doi: 10.1371/journal.pcbi.1011099. eCollection 2023 May.

Abstract

The druggability of small-molecule binding sites can be significantly affected by protein motions and conformational changes. Ligand binding, protein dynamics and protein function have been shown to be closely interconnected in myosins. The breakthrough discovery of omecamtiv mecarbil (OM) has led to an increased interest in small molecules that can target myosin and modulate its function for therapeutic purposes (myosin modulators). In this work, we use a combination of computational methods, including steered molecular dynamics, umbrella sampling and binding pocket tracking tools, to follow the evolution of the OM binding site during the recovery stroke transition of human β-cardiac myosin. We found that steering two internal coordinates of the motor domain can recapture the main features of the transition and in particular the rearrangements of the binding site, which shows significant changes in size, shape and composition. Possible intermediate conformations were also identified, in remarkable agreement with experimental findings. The differences in the binding site properties observed along the transition can be exploited for the future development of conformation-selective myosin modulators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cardiac Myosins* / chemistry
  • Cardiac Myosins* / metabolism
  • Heart
  • Humans
  • Myocardium / metabolism
  • Myosins / chemistry
  • Urea / metabolism
  • Ventricular Myosins* / chemistry
  • Ventricular Myosins* / metabolism

Substances

  • Cardiac Myosins
  • Ventricular Myosins
  • Myosins
  • Urea

Grants and funding

This work was supported by the EPSRC through the Doctoral Training Partnership with Queen Mary University of London (grant no. EP/R513106/1 to FA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.