ArticleThe journal of physical chemistry. B2025
Unraveling Mutation-Induced Protein Communication Pathways in the Actomyosin Complex: Insights from Comprehensive Metadynamics Simulations.
Article in The journal of physical chemistry. B, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Mutation-induced free-energy remodeling of recovery stroke and ATP hydrolysis in human cardiac β-myosin.Biophysical journal · 2026Article
- A song of heads and tails: myosin II conformational regulation and filament dynamics shape force generation in non-muscle cells.Biophysical reviews · 2026Review
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3 authors.
Funding
Abstract
The binding of myosin to the actin filament in the cardiac thin filament (CTF) plays a critical role in regulating normal contraction and relaxation. Hereditary mutations in human β-cardiac myosin can result in severe manifestations of heart failure. However, despite its significance, how these mutations create contractile dysfunction and eventually drive pathogenic heart remodeling remains unknown. The effect of mutations on the conformational free energy barriers between different states of the actomyosin complex remains elusive. Mutations can transmit effects across many angstroms in protein complexes, affecting multiple associated proteins and thereby altering function. To investigate the effect of point mutations in myosin on the free energy barriers of ADP release and the conformational transitions of myosin and tropomyosin (Tm) from the ADP-bound to the Rigor state, we employed metadynamics simulations on the wild-type (WT) and three myosin-mutated actomyosin complexes (Arg403Gln (R403Q), Arg453Cys (R453C), and Glu525Lys (E525K)). Our calculations demonstrated that point mutations in myosin notably influence its conformational flexibility. Additionally, we observed that all of the mutations studied caused a significant reduction in the free energy barriers for ADP release from the actomyosin complex. Moreover, we found substantial effects of mutations on the free energy barriers to conformational transitions in the myosin. Furthermore, calculations show the transmission effects of the conformational flexibility of myosin on the conformational transition free energy surface of Tm through stronger electrostatic interactions between the binding residues of myosin and Tm. Such changes in the free energy barriers by a myosin mutation within the actomyosin complex allosterically impact other components by inducing structural and dynamic alterations that ultimately lead to pathogenic effects on filament function.
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