Predicting the effects of dATP on cardiac contraction using multiscale modeling of the sarcomere.

ABSTRACT: 2'-deoxy-ATP (dATP) is a naturally occurring small molecule that has shown promise as a therapeutic because it significantly increases cardiac myocyte force development even at low dATP/ATP ratios. To investigate mechanisms by which dATP alters myosin crossbridge dynamics, we used Brownian dynamics simulations to calculate association rates between actin and ADP- or dADP-bound myosin. These rates were then directly incorporated in a mechanistic Monte Carlo Markov Chain model of cooperative sarcomere contraction. A unique combination of increased powerstroke and detachment rates was required to match experimental steady-state and kinetic data for dATP force production in rat cardiac myocytes when the myosin attachment rate in the model was constrained by the results of a Brownian dynamics s

SUBMITTER: McCabe KJ 

PROVIDER: S-EPMC7721865 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature