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

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. Since there are no crystal structures for hERG channels, creation and validation of its reliable atomistic models have been key targets in molecular cardiology for the past decade. In this study, we developed and vigorously validated models for open, closed, and open-inactivated states of hERG1 using a multistep protocol. The conserved elements were derived using multiple-template homology modeling utilizing available structures for Kv1.2, Kv1.2/2.1 chimera, and KcsA channels. Then missing elements were modeled with the ROSETTA De Novo protein-designing suite and further refined with all-atom molecular dynamics simulations. The final ensemble of models was evaluated for consistency to the reported experimental data from biochemical, biophysical, and electrophysiological studies. The closed state models were cross-validated against available experimental data on toxin footprinting with protein-protein docking using hERG state-selective toxin BeKm-1. Poisson-Boltzmann calculations were performed to determine gating charge and compare it to electrophysiological measurements. The validated structures offered us a unique chance to assess molecular mechanisms of state-dependent drug binding in three different states of the channel.

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.…”

“…The open state was modeled using Kv1.2-2.1 chimeric channel chain B (PDB ID code 2R9R) (20) as the template, and the closed state was modeled with several reported closed-state models (21). The modeling protocol was similar to that used in state-dependent modeling of hERG channel by Durdagi et al (42).…”

A human ether-á-go-go-related (hERG) ion channel atomistic model generated by long supercomputer molecular dynamics simulations and its use in predicting drug cardiotoxicity

“…Since most hERG blockers access the inner hERG cavity in the channel's open state (Mitcheson et al, 2000;Spector et al,1996), an open-state model (Durdagi et al, 2012) was used as an initial configuration for the MD. Nonetheless, relevant future work will investigate drugs that bind to other states of the hERG channel that could interfere with its subsequent functional recycling.…”

In silicoinvestigation of PARP-1 catalytic domains inholoandapostates for the design of high-affinity PARP-1 inhibitors

“…They were docked into the central cavities of previously generated and validated human ether-a go-go related gene (hERG1) K-channel models by our group [12][13][14][15][16][17][18][19] . Table 2 shows the Glide/XP docking scores of these drugs in hERG1.…”

“…It is well established that human ether-à-go-go related gene 1 (hERG1) K channel is overexpressed in many tumors and, therefore, pro-arrhythmic potential of all novel inhibitors is an important concern in structure driven drug development. To circumvent potential risks associated with druginduced QT prolongation, we report on an in silico cardiotoxicity screening against previously developed hERG1 models [12][13][14][15][16][17][18][19] by our group.…”