Predicting Effects of Tropomyosin Stiffness on Cardiac Muscle Contraction Using Coarse-Grained Stochastic Modeling

Abstract

During the cardiac thin filament activation process, Tropomyosin (Tm) oscillates over the surface of actin filament in the azimuthal direction to regulate the access of Myosin heads to actin binding sites. These dynamical modes of oscillation and the resultant cooperative activation effects depend critically on the stiffness characteristics and the mobility of Tm molecules. In this study, we developed a stochastic coarse-grained computational model to describe the Tm motions over the surface of actin filament using Langevin-Brownian dynamics. The model represents the structural arrangement of Tm molecules as a flexible chain with variable torsional stiffness using a crystal elastic network approach. The model accounts for the spatial interactions among nearest-neighbor regulatory units (RUs), which are thought to appear from the structural coupling of adjacent Tropomyosins. This elastic coupling between RUs is accomplished by assigning a multi-well potential energy for each RU. The model is then used to study the effects of Tm torsional stiffness variations on the cooperative activation of the thin filament. The results suggest that small perturbations in Tm torsional stiffness can lead to a significant effect on force-Ca2+ sensitivity, the rate of tension redevelopment, relaxation rate, and other contraction characteristics. The present stochastic computational model draws for the first time a more detailed molecular connection between Tm torsional stiffness, Tm modes of oscillations over actin surface, cooperativity among RUs, and dynamic muscle twitches. Thus, this coarse-graining approach may be useful in explaining many cardiomyopathies induced by structural remodeling and stiffening in Tm molecules as a result of point mutations in the human gene TPM1.