Structural and Functional Impact of Amino Acid Substitution on Calmodulin Binding in Cardiac Myocytes

Calmodulin (CALM) is an important protein involved in numerous signaling processes, acting through induced conformational changes in response to local calcium concentration. In the cardiac myocyte, CALM binds to several important components involved in excitation, in particular L-type Calcium Channels (LTCC), Cardiac Ryanodine Receptors (RYR2), and Calcium/Calmodulin-dependent protein Kinase II (CaMKII). CALM plays a role in LTCC and RYR2 channel dynamics through direct binding interactions and through CaMKII-dependent phosphorylation. Recent studies into the impact of specific single nucleotide polymorphisms (SNPs) in CALM have been linked to specific changes in the behavior of LTCC's and RyR2's and also to various cardiac disease states (e.g. Long QT Syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia). In addition, additional CALM SNPs have been observed in publicly available genomic databases based upon genomic sequencing of the general human population and these SNPs that have not yet been functionally classified. Using a computational mutagenesis approach based on Delaunay tessellation and statistical geometry, the impact of specific SNPs on the structural stability of CALM-binding interactions has been predicted. These predictions indicate the likelihood that a specific SNP mutation alters CALM structure and thereby its function. Results indicate certain SNP mutations have a differential impact on CALM binding stability to its various targets. Deeper analysis of CALM structure suggests the possible underlying mechanism by which these mutations can cause cardiac disease and may explain why certain mutations correlate with a particular disease state.