Key result
Molecular dynamics simulations of the hERG potassium channel identified two permeation pathways, with the vacancy diffusion mechanism showing a lower energy barrier of about 6 kcal/mol.
Atomistic simulations suggest the low conductance of the hERG channel is due to a vacancy diffusion mechanism with a ~6 kcal/mol energy barrier, differing from the knock-on mechanism of high-conductance channels.
Provides atomic-level hERG insights for drug screening models; leaves open validation in native cardiac channels.
The inward rectifier voltage-gated potassium channel hERG is of primary importance for the regulation of the membrane potential of cardiomyocytes. Unlike most voltage-gated K(+)-channels, hERG shows a low elementary conductance at physiological voltage and potassium concentration. To investigate the molecular features underlying this unusual behavior, we simulated the ion conduction through the selectivity filter at a fully atomistic level by means of molecular dynamics-based methods, using a homology-derived model. According to our calculations, permeation of potassium ions can occur along two pathways, one involving site vacancies inside the filter (showing an energy barrier of about 6 kcal mol(-1)), and the other characterized by the presence of a knock-on intermediate (about 8 kcal mol(-1)). These barriers are indeed in accordance with a low conductance behavior, and can be explained in terms of a series of distinctive structural features displayed by the hERG ion permeation pathway.
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Ceccarini et al. (2012) studied hERG Potassium Channel function. Molecular dynamics simulations of the hERG potassium channel identified two permeation pathways, with the vacancy diffusion mechanism showing a lower energy barrier of about 6 kcal/mol.
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