(723i) Multiscale Coarse-Grained Model of Actin Filaments and Its Predictions of Compressive and Tensile Deformations on Filament Composition

Actin filaments act as the fundamental framework of a cell imparting diverse functionalities such as motility, cell division, and transportation of cargo. The filaments constantly undergo reactions such as polymerization, depolymerization, ATP hydrolysis, and inorganic phosphate (Pi) release. These reactions dictate the binding of various actin-binding proteins (ABPs) resulting in the formation of several higher-order structures such as cross-linked networks, bundled filaments, branched filaments, and so on. Understanding the pathways governing the formation of these higher-order structures, which occur on multiple timescales, by atomistic simulations is computationally infeasible. In this regard, a multiscale ultra-coarse-grained model of actin filaments, developed earlier [Katkar et al., Biophysical Journal, 115, 1589-1602, 2018], was extended in this work to gain insight into the reactions controlling the binding of different ABPs. Specifically, we investigated the effects of external perturbations, such as compressive and tensile strains, on the rate of filament depolymerization, ATP hydrolysis, and Pi release. These strains mimic the action of actin-binding proteins that typically induce structural changes in the filament. Results elucidating the effects of strains at a single actin filament level as well as at cellular levels using Markov State Models (MSM) will be presented. Furthermore, connections explaining the experimental observations of cooperative binding of certain ABPs such as cofilin will be made. Finally, the usefulness of such a multiscale model in a broader context will be discussed briefly.