|Authors||K. J. McCabe, Y. Aboelkassem, S. Dewan, M. Regnier and A. D. McCulloch|
|Title||A Markov State Model of the Sarcomere to Explain the Effects of dATP on Cardiac Contraction|
|Project(s)||No Simula project|
|Year of Publication||2018|
|Place Published||Biophysical Society 62nd Annual Meeting, San Francisco CA|
2-deoxy-ATP is a naturally occurring homolog of ATP known to increase force production, enhance crossbridge cycling speed, and accelerate the removal of Ca2+ from the cytoplasm during cardiac muscle cell relaxation. At low ratios of dATP to ATP in cardiomyocytes, steady state force has been shown to increase nonlinearly at physiological [Ca2+]1. The purpose of this study is to discover specific mechanisms by which dATP alters myosin dynamics within the sarcomere using multiscale computational modeling. We have developed a comprehensive mechanistic Monte Carlo Markov State model of rat sarcomere contraction which includes cooperativity in both thin filament activation and crossbridge cycling through nearest-neighbor Tropomyosin (Tm) interactions as well as cross bridge attachment effect on neighboring myosin on the thick filament. This novel sarcomere model was used to test the effects of dATP on contractility within the sarcomere. We combined experimental data on the subcellular, cellular, and organ level as well as Molecular Dynamics (MD) data to parameterize and validate the model. We tested combinations of 4 possible kinetic transitions in which dATP is hypothesized to affect crossbridge cycling and tested various degrees of cooperativity in the system to find a likely combination of mechanisms by which dATP affects contraction.