Binding pocket dynamics along the recovery stroke of human β-cardiac myosin
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Binding pocket dynamics along the recovery stroke of human β-cardiac myosin. / Akter, Fariha; Ochala, Julien; Fornili, Arianna.
I: PLOS Computational Biology, Bind 19, Nr. 5, e1011099, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Binding pocket dynamics along the recovery stroke of human β-cardiac myosin
AU - Akter, Fariha
AU - Ochala, Julien
AU - Fornili, Arianna
N1 - Publisher Copyright: 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.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85160966713&partnerID=8YFLogxK
U2 - 10.1371/journal.pcbi.1011099
DO - 10.1371/journal.pcbi.1011099
M3 - Journal article
C2 - 37200380
AN - SCOPUS:85160966713
VL - 19
JO - P L o S Computational Biology (Online)
JF - P L o S Computational Biology (Online)
SN - 1553-734X
IS - 5
M1 - e1011099
ER -
ID: 356880734