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Dynamics of the Pre-Powerstroke Myosin Lever Arm and the Effects of Omecamtiv Mecarbil.

Authors :
Childers MC
Regnier M
Source :
International journal of molecular sciences [Int J Mol Sci] 2024 Sep 27; Vol. 25 (19). Date of Electronic Publication: 2024 Sep 27.
Publication Year :
2024

Abstract

The binding of small molecules to sarcomeric myosin can elicit powerful effects on the chemomechanical cycle, making them effective therapeutics in the clinic and research tools at the benchtop. However, these myotropes can have complex effects that act on different phases of the crossbridge cycle and which depend on structural, dynamic, and environmental variables. While small molecule binding sites have been identified crystallographically and their effects on contraction studied extensively, small molecule-induced dynamic changes that link structure-function are less studied. Here, we use molecular dynamics simulations to explore how omecamtiv mecarbil (OM), a cardiac myosin-specific myotrope, alters the coordinated dynamics of the lever arm and the motor domain in the pre-powerstroke state. We show that the lever arm adopts a range of orientations and find that different lever arm orientations are accompanied by changes in the hydrogen bonding patterns near the converter. We find that the binding of OM to myosin reduces the conformational heterogeneity of the lever arm orientation and also adjusts the average lever arm orientation. Finally, we map out the distinct conformations and ligand-protein interactions adopted by OM. These results uncover some structural factors that govern the motor domain-tail orientations and the mechanisms by which OM primes the pre-powerstroke myosin heads.

Details

Language :
English
ISSN :
1422-0067
Volume :
25
Issue :
19
Database :
MEDLINE
Journal :
International journal of molecular sciences
Publication Type :
Academic Journal
Accession number :
39408754
Full Text :
https://doi.org/10.3390/ijms251910425