Abstract 9671: Molecular Dynamics and Calcium Binding Studies on Troponin Mutations Causing Dilated Cardiomyopathy
Troponin (Tn), part of the thin filament in cardiomyocytes, plays an important role in calcium signaling events in cardiac muscle contraction. It acts as a Ca2+-dependent switch, activating and deactivating the myofilament leading to contraction and relaxation of the muscle cell. The most common form of heart muscle disease, dilated cardiomyopathy (DCM), is characterized by dilatation of the heart and impaired systolic function of the left or both ventricles. Several Tn mutations that cause DCM have been reported. We used microsecond timescale molecular dynamics (MD) simulations to elucidate the molecular action of three troponin C (TnC) DCM mutations - D75Y, E59D and G159D - with particular focus on calculating the free energy difference between the open and closed states of the TnC as well as average times between opening events. We found free energy differences between the open and closed states of ~8 kcal/mol for the wildtype system. While G159D causes a significant increase in the free energy difference (by ~4 kcal/mol), D75Y does not change the free energy difference significantly, and E59D even causes a ~2 kcal/mol drop in the free energy difference. This finding illustrates nicely that the opening propensity of the TnC hydrophobic patch is only one possible mechanism by which DCM mutations can influence the contractility in cardiomyocytes. Both G159D and E59D use this mechanism. D75Y, however, does not influence TnI binding but rather impacts Ca2+-binding affinity, which can also be observed in our Brownian Dynamics simulations of calcium association.
- © 2013 by American Heart Association, Inc.