Cardiomyopathy Mutations in Actomyosin: A Tertiary Structure Dynamics Approach within an in Silico Optical Trap Experiment

Abstract

Despite great success in simulating protein energetics, molecular dynamics approaches are currently too computationally intensive for use in studying supramolecular actomyosin assemblies. Here tertiary structure coarsegraining strategies are developed to create low-dimension potential functions (Tertiary Structure Models, or TSM) from MD-generated statistical potentials. The effect of domain selection is probed through comparison of successively finer coarsening, beginning with a 4-domain (lever-arm + converter, upper 50k, lower 50k, and n-terminal) TSM. In an attempt to discern and reproduce the basic characteristics of the power stroke the TSM is parameterized for the pre- and post-powerstroke states based on the scallop crystal structures 1qvi and 2ovk, respectively.A first implementation of this approach to study the mechanical effect of mutations in the myosin actin-binding regions is presented in a rigid-body dynamics simulation of domain motion within an in silico optical trap experiment. Both the S532P and R403Q mutations to the myosin S1 are known to cause cardiomyopathy. It is known that the S532P mutation in the lower 50k domain decreases step size from wild-type while the R403Q mutation shows no difference with wild-type within the optical trap experiment. The differential effect of two mutations both occurring in the actin-binding regions is probed within simulation through alterations to the binding parameters of the upper 50k and lower 50k domains with actin. The ability of the TSM model to capture these fundamental results is used as a validation of the approach.