Investigation of the Recovery Stroke and ATP Hydrolysis and Changes Caused Due to the Cardiomyopathic Point Mutations in Human Cardiac β Myosin

Ananya Chakraborti, Anthony P. Baldo, Jil C Tardiff, Steven D. Schwartz

Research output: Contribution to journalArticlepeer-review

Abstract

Human cardiac β myosin undergoes the cross-bridge cycle as part of the force-generating mechanism of cardiac muscle. The recovery stroke is considered one of the key steps of the kinetic cycle as it is the conformational rearrangement required to position the active site residues for hydrolysis of ATP and interaction with actin. We explored the free-energy surface of the transition and investigated the effect of the genetic cardiomyopathy causing mutations R453C, I457T, and I467T on this step using metadynamics. This work extends previous studies onDictyosteliummyosin II with engineered mutations. Here, like previously, we generated an unbiased thermodynamic ensemble of reactive trajectories for the chemical step using transition path sampling. Our methodologies were able to predict the changes to the dynamics of the recovery stroke as well as predict the pathway of breakdown of ATP to ADP and HPO42-with the stabilization of the metaphosphate intermediate. We also observed clear differences between theDictyosteliummyosin II and human cardiac β myosin for ATP hydrolysis as well as predict the effect of the mutation I467T on the chemical step.

Original languageEnglish (US)
Pages (from-to)6513-6521
Number of pages9
JournalJournal of Physical Chemistry B
Volume125
Issue number24
DOIs
StatePublished - Jun 24 2021

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

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