Dilated and hypertrophic cardiomyopathies (DCM and HCM) affect 1 in 500 Americans. Current treatments only slow disease progression without treating underlying mechanisms; therefore, novel therapeutics are needed to treat HCM and DCM. 2’-deoxy-adeninetripohsphate is a naturally occurring myosin activator, and proposed heart failure and DCM therapeutic. In this work, I use molecular simulations to understand the mechanism by which dATP increase cardiac contractile force and function. Specifically, I have used molecular dynamics simulations to build Markov models of protein kinetics, that can be used with Brownian dynamics simulations to understand actin-myosin kinetics. Through this work, have shown that dATP functions by increasing the association rate of myosin to actin in the pre-powerstroke state. The DCM mutations A223T and S532P found cardiac myosin heavy chain were also modeled with this framework and found to have diverging effects on the association rate of myosin to actin. Specifically, dATP, S532P and A223T have 5.3-, 3.0-, and 0.56-time fold changes to the association rate respectively. These simulations help to predict organ level function, and lead to improved mechanistic understandings of actin-myosin interactions.

The video of this presentation is available here.