Low resolution protein mapping and KB-R7943 drug-protein molecular interaction analysis of long-QT syndrome linked KCNH2 mutations

Cardiac Arrhythmias (CA) are responsible for syncope and sudden cardiac death (SCD) in several million cases worldwide. The molecular basis of CA pathogenesis is known, but the underlying mechanisms connecting genotype to phenotype changes in the proteins are not yet fully explored. Hence, in this study, three LQT2-linked missense mutations (Thr613Met, Ser641Phe and Gly648Ser) located in exon-7 region of KCNH2 gene identified in CA patients was assessed for their deleteriousness using diverse computational algorithms. The SIFT and PolyPhen-2 methods, which depends on sequence conservation across species, and protein structure-based information have attributed pathogenicity to these variants. Protein behavior studies at 3D level have identified that these three missense mutations induce biochemically severe amino acid changes that may alters the structure and function of KCNH2. Our molecular docking suggested that mutant KCNH2 protein shows a similar binding interactions to KB-R7943 as compared to the wild type model. These findings could be useful in resorting to alternate therapies for subset of CA patients who show limited therapeutic response to KB-R7943. This study supports that in silico approaches could act as a first-line filters to screen the potential impact of CA linked KCNH2 mutations depending upon the perspective of molecular evolution and phenotype of proteins.