Development of Atomistic Models for Closed, Open and Open-Inactivated States of hERG1 Channel using Rosetta Protein Modeling Suite and Molecular Dynamics Simulations

Abstract

The human ether-a-go-go related gene 1 (hERG1) K ion channel is a key element for the rapid component of the delayed rectified potassium current in cardiac myocytes. It is essential for the normal repolarization phase of the cardiac action potential. Loss of function mutations in hERG1 cause increased duration of ventricular repolarization which leads to prolongation of the time interval between Q and T waves of the body surface electrocardiogram (long QT syndrome-LQTS). hERG1 K+ channel is a homotetramer composed of four identical homologous subunits each containing six transmembrane (TM) helices S1-S6. Single hERG channels are either closed, open or inactivated conformations depending on TM voltage. Although creation and validation of reliable 3D atomistic models of the hERG channel has been a key target in molecular cardiology for last decade, there are no reported S1-S6 TM homology models of the channel in different states yet in literature. In this study, we derived open, closed and open-inactivated states of hERG1 using ROSETTA protein modeling suite and side-chain placements are optimized by molecular dynamics simulations. Although backbone templates are modeled on available crystal structures of Kv1.2 and KcsA channels, the missing parts are modeled de novo. Final models are evaluated for consistency to the reported structural elements discovered mainly on the basis of mutagenesis and electrophysiology. Closed state models are further validated by protein-protein docking using selective peptide toxin and available experimental data on toxin foot-printing. Derived models of hERG1 in different states offer an indispensable template for rational drug design as well as better understanding of molecular mechanisms of hERG channel upon binding of openers or blockers.