ArticlePLoS computational biology2023
Binding pocket dynamics along the recovery stroke of human β-cardiac myosin.
Article in PLoS computational biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 6 citations in OpenAlex.
- Dynamics of the Pre-Powerstroke Myosin Lever Arm and the Effects of Omecamtiv Mecarbil.International journal of molecular sciences · 2024Article
- Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite opposite effects in heart contraction.Nature communications · 2024Article
- A weak coupling mechanism for the early steps of the recovery stroke of myosin VI: A free energy simulation and string method analysis.PLoS computational biology · 2024Article
- Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite antagonistic effects in heart contraction.bioRxiv : the preprint server for biology · 2023Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
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