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Predicting the effects of dATP on cardiac contraction using multiscale modeling of the sarcomere
- Source :
- Arch Biochem Biophys
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
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 simulation. Nearest-neighbor cooperativity was seen to contribute to, but not fully explain, the steep relationship between dATP/ATP ratio and steady-state force-development observed at lower dATP concentrations. Dynamic twitch simulations performed using measured calcium transients as inputs showed that the effects of dATP on the crossbridge alone were not sufficient to explain experimentally observed enhancement of relaxation kinetics by dATP treatment. Hence, dATP may also affect calcium handling even at low concentrations. By enabling the effects of dATP on sarcomere mechanics to be predicted, this multi-scale modelling framework may elucidate the molecular mechanisms by which dATP can have therapeutic effects on cardiac contractile dysfunction.
- Subjects :
- Sarcomeres
0301 basic medicine
Biochemistry & Molecular Biology
Contraction (grammar)
1.1 Normal biological development and functioning
Myosin
Biophysics
Bioengineering
Cooperativity
Cardiovascular
Biochemistry
Sarcomere
Article
03 medical and health sciences
Deoxyadenine Nucleotides
CrossBridge
Models
Brownian dynamics
Underpinning research
Predictive Value of Tests
Animals
Myocyte
Multiscale modeling
Myocytes, Cardiac
heterocyclic compounds
Molecular Biology
Actin
Myocytes
030102 biochemistry & molecular biology
Chemistry
Myocardium
Models, Cardiovascular
Myocardial Contraction
Rats
enzymes and coenzymes (carbohydrates)
Heart Disease
030104 developmental biology
Cardiac contractility
Biochemistry and Cell Biology
Cardiac
Subjects
Details
- ISSN :
- 00039861
- Volume :
- 695
- Database :
- OpenAIRE
- Journal :
- Archives of Biochemistry and Biophysics
- Accession number :
- edsair.doi.dedup.....ac51328e85fd3c680fd8e9d2217f540e