Computational Modeling of Sarcomere Protein Mutations and Drug Effects on Cardiac Muscle Behavior

Abstract

Hypertrophic and Dilated Cardiomyopathies are caused by inherited mutations in sarcomeric proteins: Myosin (M), Troponin (Tn), Tropomyosin (Tm) and Myosin Binding Protein-C (MyBP-C). A quantitative understanding of how mutations change protein behaviour, and hence cardiac muscle contraction, and how adaptations to these changes result in disease, could accelerate the design of novel personalized treatments and therapeutics. Newly developed multiscale computational tools, tightly interlaced with multiple experiments, can enhance efforts to correct the problems associated with cardiomyopathies and prevent or more effectively manage the disease. Using these computational tools, we examined the effects of mutations in myosin and troponin on cardiac muscle contractility and overall heart functional behaviour. We also examined the effects of potential therapeutics that modulate protein interactions and cardiac muscle contractility.