a markov state model of the sarcomere to explain the effects of datp on cardiac contraction
Name: Kimberly Joan McCabe
Grad Year: 2019
2-deoxy-ATP is a naturally occurring homolog of ATP. dATP is known to increase force production, enhance crossbridge cycling speed, and accelerate the removal of Ca2+ from the cytoplasm during cell relaxation in vitro as well as in animal models. At low ratios of dATP to ATP in cells, steady state force has been shown to increase nonlinearly at physiological [Ca2+], while at higher ratios the relationship becomes linear. Thus, dATP has shown promise as a potential therapeutic because it creates significant increases in force even at low dATP/ATP ratios. 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 interactions due to overlapping Tropomyosin (Tm) molecules on the actin thin 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 data to parameterize and validate the model. We tested combinations of 4 different 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.
Industry Application Area(s)
Life Sciences/Medical Devices & Instruments