A spatially-detailed model of actin and myosin interaction in the cardiac myofilament including strain-based rates and cooperative mechanisms

Abstract

The availability of increased computing power will make new classes of biological models possible. One such class will be spatially-explicit representations of subcellular machinery. We have developed such a model of the interaction of actin and myosin within one pair of thick and thin filaments in the cardiac sarcomere. We have chosen to model the smallest repeating unit that maintains fundamental spatial interactions thought to produce important and characteristic cardiac muscle responses at cell, tissue and whole heart levels. The model discussed differs from existing models by having spatially-explicit representations of actin, myosin, regulatory protein interactions including extensible links to capture filament compliances. Sample results are compared with experimental characterizations of real muscle. The model recapitulates a wide range of complex, non-linear behavior and hence provides a plausible and quantitative explanation for several unexplained phenomena in cardiac muscle. The execution of the model demands Monte Carlo-based simulations of Markov representations of Ca regulation and actin-myosin interactions with strain-dependent rates. In addition, the solution of the compliant realignment of the thick and thin filament binding sites requires an iterative solution technique that demands substantial computational resources. The model is suitable to serve as a basis for larger scale simulations.