Modeling the Global Dynamics of the Tropomyosin-Actin Molecular Switch that Governs Cardiac Cell Contraction*

Cell contraction in healthy and diseased cardiac tissue is driven by the cyclic binding events of myosin-thick filament motor proteins along the tropomyosin entwined actin thin-filament. Prior work has shown that the azimuthal transitioning of the tropomyosin chain around actin regulates myosin attachment via three main equilibrium states. Although Molecular Dynamics simulations have resolved the atomistic structures associated with each of these states, they are computationally inefficient at capturing the millisecond-scale non-equilibrium dynamics of the tropomyosin-actin complex and their cascading effects on myosin binding. In this project, we utilize Elastic Network Modelling to construct a coarse-grain representation of thin filament dynamics and characterize possible actin-myosin coupling events. The major interacting amino-acid residues of the tropomyosin and actin structures are respectively denoted as structural nodes of the network and their connections are expanded as harmonic potentials, with both mechanical and chemical constraint components. Next, we determine the normal modes of interaction between the proteins and characterize their corresponding shape and motion regimes. Finally, we couple our model to a recent CryoEM analysis of myosin structure to outline a theory for the collective activation of thin and thick filaments.