title: Dynamics of the EAG1 K+channel selectivity filter assessed by molecular dynamics simulations.
abstract: EAG1 channels belong to the KCNH family of voltage gated potassium channels. They are expressed in several brain regions and increased expression is linked to certain cancer types. Recent cryo-EM structure determination finally revealed the structure of these channels in atomic detail, allowing computational investigations. In this study, we performed molecular dynamics simulations to investigate the ion binding sites and the dynamical behavior of the selectivity filter. Our simulations suggest that sites S2 and S4 form stable ion binding sites, while ions placed at sites S1 and S3 rapidly switched to sites S2 and S4. Further, ions tended to dissociate away from S0 within less than 20 ns, due to increased filter flexibility. This was followed by water influx from the extracellular side, leading to a widening of the filter in this region, and likely non-conductive filter configurations. Simulations with the inactivation-enhancing mutant Y464A or Na+ions lead to trapped water molecules behind the SF, suggesting that these simulations captured early conformational changes linked to C-type inactivation.
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Althanstraße 14, 1090 Vienna, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Bernsteiner
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Althanstraße 14, 1090 Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Bründl
authors.affiliation: Department of Pharmacology and Toxicology, University of Vienna, Althanstraße 14, 1090 Vienna, Austria. Electronic address: anna.stary@univie.ac.at.
authors.forename: Anna
authors.initials: A
authors.lastname: Stary-Weinzinger
mesh_terms: D020285:Cryoelectron Microscopy; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human
keywords: C-type inactivation; Ion binding sites; KCNH1 channel; Molecular dynamics simulation; Na(+) binding sites; Y464A mutant