title: 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 (LQTS) in humans. 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 have been a key target in molecular cardiology and pharmacology for the last decade. Although 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 transmembrane segments. We tested a template-driven de-novo design with ROSETTA-membrane modeling using side-chain placements optimized by subsequent molecular dynamics (MD) simulations. Although 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 with that established by toxin foot-printing and nuclear magnetic resonance studies. Implications of the refined hERG1 model to binding of blockers and channels activators (potent new ligands for channel activations) are discussed.
authors.affiliation: Department of Biological Sciences, Institute for Biocomplexity and Informatics, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Julia
authors.initials: J
authors.lastname: Subbotina
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yarov-Yarovoy
authors.forename: James
authors.initials: J
authors.lastname: Lees-Miller
authors.forename: Serdar
authors.initials: S
authors.lastname: Durdagi
authors.forename: Jiqing
authors.initials: J
authors.lastname: Guo
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Duff
authors.forename: Sergei Yu
authors.initials: SY
authors.lastname: Noskov
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D002462:Cell Membrane / Q000502:physiology*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015640:Ion Channel Gating; D008564:Membrane Potentials; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human