For Whom the Heart Tolls: Development of a Molecular Description for Cardiac Muscle Function

Though the function of striated muscle is pertinent to human life, a molecular description of this complex system still escapes modern understanding. To further obscure this determination in the case for cardiac muscle, single point mutations to the proteins of striated muscle have been associated with the development of a type of cardiac disease known as cardiomyopathies, which result in a reconstruction of the heart morphology. In this dissertation, I present computational studies utilizing molecular dynamics (MD) simulations for determining native and mutagenic functions of the two main protein complexes of cardiac muscle, the thin and thick filament. The first project categorizes point mutation induced changes to a conformational change known as the recovery stroke with metadynamics, an enhanced sampling method, as well as the mechanism of enzymatic hydrolysis with transition path sampling (TPS) in a non-human isoform of the thick filament. The second project follows a similar determination as in the previously mentioned project. However, in this case, the examination was performed for a human cardiac isoform of the thick filament and determined differences between the two isoforms for the enzymatic mechanism as well as categorized the mutagenic changes to the recovery stroke due to point mutations associated with the development of cardiomyopathies. The third project outlines the dynamics and thermodynamics of a conformational change of the thin filament required in the muscle contraction cascade. Metadynamics was employed to model tropomyosin movement in the thin filament from an "inactive" state to an "active" state, while identifying potentially preferential thick filament interaction sites on the thin filament. Lastly, MD simulations of the thin filament in conjunction with experimental measurements was utilized to characterize possible conformations of an inherently unstructured region of the filament that has escaped experimental categorization.The work presented here provides a basis for studying the complex native and mutagenic behavior of the protein complexes for cardiac muscle, while also providing additional structural detail down to the atomic level. Not only do they highlight important details about the specific biological processes of these protein complexes mentioned, but the methods presented could be easily extended to look at the other remaining and numerous processes undergone by these complexes as well as extend this type of analysis to study the complex behavior of other biological systems