Structural refinement of the hERG1 pore and voltage‐sensing domains with ROSETTA‐membrane and molecular dynamics simulations

Abstract

The hERG1 gene (Kv11.1) encodes a voltage-gated potassium channel. Mutations in this gene, lead to one form of the Long QT Syndrome in humans (LQTS). Promiscuous binding of drugs to hERG1 is known to alter the structure/function of the channel leading to an acquired form of the LQTS. Expectably, creation and validation of reliable 3D model of the channel has been a key target in molecular cardiology and pharmacology for the last decade. While many models were built, they all were limited to pore domain. In this work, a full model of the hERG1 channel is developed which includes all trans-membrane segments. We tested a template-driven de-novo design with ROSETTA-membrane modeling using side-chain placements optimized by subsequent molecular dynamics (MD) simulations. While backbone templates for the homology modeled parts of the pore and voltage sensors were based on the available structures of KvAP, Kv1.2 and Kv1.2–Kv2.1 chimera channels, the missing parts are modeled de-novo. The impact of several alignments on the structure of the S4 helix in the voltage-sensing domain was also tested. Herein, final models are evaluated for consistency to the reported structural elements discovered mainly on the basis of mutagenesis and electrophysiology. These structural elements include: salt bridges and close contacts in the voltage-sensor domain; and the topology of the extracellular S5-pore linker compared to that established by toxin foot-printing and NMR studies. Implications of the refined hERG1 model to binding of blockers and channels activators (potent new ligands for channel activations) are discussed.

Hydrophobic plug functions as a gate in voltage-gated proton channels

“…It should be stressed that in addition to small differences in alignments chosen in these different studies, there are also many methodological differences, such as the modeling of side-chain packing and the combination of de novo ROSETTA-membrane and homology modeling in an iterative routine. Our approach (42,43) was tested rigorously on models of voltage-gated potassium hERG channels (42) and secondary transporters (44) and was found to be consistent with independent experimental data.…”

Modeling of Open, Closed, and Open-Inactivated States of the hERG1 Channel: Structural Mechanisms of the State-Dependent Drug Binding

“…The previously published sequence alignment was used 13 Loop modeling is one of the key components in homology modeling as it participates in many biological events and functional aspects such as ligand−receptor interactions. However, due to their flexible/dynamic nature, it is often very difficult to predict their native conformations.…”

hERG K+Channels: Structure, Function, and Clinical Significance

“…Based on sequence homology to potassium and cyclic nucleotide-gated channels with known structures, numerous homology models of the Kv11.1 channel have been constructed (304,343,591,603,628,646,705). The homology models have usually included only the pore domain regions, with the focus being on structural basis of ion permeation or drug binding.…”