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

Autor: Akter F; Department of Chemistry, School of Physical and Chemical Sciences, Queen Mary University of London, London, United Kingdom., Ochala J; Department of Biomedical Sciences, University of Copenhagen, København N, Denmark.; Centre of Human and Applied Physiological Sciences, King's College London, London, United Kingdom., Fornili A; Department of Chemistry, School of Physical and Chemical Sciences, Queen Mary University of London, London, United Kingdom.
Jazyk: angličtina
Zdroj: PLoS computational biology [PLoS Comput Biol] 2023 May 18; Vol. 19 (5), pp. e1011099. Date of Electronic Publication: 2023 May 18 (Print Publication: 2023).
DOI: 10.1371/journal.pcbi.1011099
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 Akter et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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