Modeling the Human KCNQ1 Potassium Ion Channel: Application of Computational Approaches to Cardiotoxicity

KCNQ1 (Kv7.1) is a voltage gated potassium ion channel and one of the most important cationic channels responsible for initiating the slow delayed rectifier (IKs) current in the atrial and ventricular myocytes. Mutations in... [ view full abstract ]

KCNQ1 (Kv7.1) is a voltage gated potassium ion channel and one of the most important cationic channels responsible for initiating the slow delayed rectifier (IKs) current in the atrial and ventricular myocytes. Mutations in KCNQ1 have been implicated in a wide range of cardiac diseases, such as the long QT syndrome (LQT1/LQT5), congenital atrial fibrillation and short QT syndrome. Thus, studying the fine structural details of this important ion channel associated with the KCNE1 beta subunit will enhance our understanding of different physiologically and pathophysiologically observed phenomena. At present, very few complete models for human cardiac ion channels have been generated, and this is due to several factors mainly related to the lack of detailed experimental crystal and/or NMR structures.
Our methodology combined homology modeling of KCNQ1 using a paddle chimera channel as a template for the transmembrane domains. The NMR structure of the auxiliary subunit, KCNE1 was exposed to adjustments and molecular dynamic (MD) refinement. The complete models were refined using ModeRefiner and FG-MD tools, and validated with PROCHECK. The final model of KCNQ1 tetramer was used for docking the KCNE1 protein and further exposed to MD simulation using NAMD package.
In this study, we are reporting a complete homology model for the open state of KCNQ1/KCNE1 cardiac ion channel along with the most recent experimental details. The current study provides valuable insights into the structure of this ion channel and opens door to future cardiotoxicity studies of drugs using computational approaches.