Identifying Key Binding Interactions Between the Cardiac L-Type Calcium Channel and Calmodulin Using Molecular Dynamics Simulations.

Defects in the binding of the calcium sensing protein calmodulin (CaM) to the L-type calcium channel (Ca V 1.2) or to the ryanodine receptor type 2 (RyR2) can lead to dangerous cardiac arrhythmias with distinct phenotypes, such as long-QT syndrome (LQTS) and catecholaminergic ventricular tachycardia (CPVT). Certain CaM mutations lead to LQTS while other mutations lead to CPVT, but the mechanisms by which a specific mutation can lead to each disease phenotype are not well-understood. In this study, we use long, 2 μs molecular dynamics simulations and a multitrajectory approach to identify the key binding interactions between the IQ domain of Ca V 1.2 and CaM. Five key interactions are found between Ca V 1.2 and CaM in the C-lobe, 1 in the central linker, and 2 in the N-lobe. In addition, while 5 key interactions appear between residues 120-149 in the C-lobe of CaM when it interacts with Ca V 1.2, only 1 key interaction is found within this region of CaM when it interacts with the RyR2. We show that this difference in the distribution of key interactions correlates with the known distribution of CaM mutations that lead to LQTS or CPVT. This correlation suggests that a disruption of key binding interactions is a plausible mechanism that can lead to these two different disease phenotypes.