title: Atomistic Modeling of Ion Conduction through the Voltage-Sensing Domain of the Shaker K+Ion Channel.
abstract: Voltage-sensing domains (VSDs) sense changes in the membrane electrostatic potential and, through conformational changes, regulate a specific function. The VSDs of wild-type voltage-dependent K+, Na+, and Ca2+channels do not conduct ions, but they can become ion-permeable through pathological mutations in the VSD. Relatively little is known about the underlying mechanisms of conduction through VSDs. The most detailed studies have been performed on Shaker K+channel variants in which ion conduction through the VSD is manifested in electrophysiology experiments as a voltage-dependent inward current, the so-called omega current, which appears when the VSDs are in their resting state conformation. Only monovalent cations appear to permeate the Shaker VSD via a pathway that is believed to be, at least in part, the same as that followed by the S4 basic side chains during voltage-dependent activation. We performed μs-time scale atomistic molecular dynamics simulations of a cation-conducting variant of the Shaker VSD under applied electric fields in an experimentally validated resting-state conformation, embedded in a lipid bilayer surrounded by solutions containing guanidinium chloride or potassium chloride. Our simulations provide insights into the Shaker VSD permeation pathway, the protein-ion interactions that control permeation kinetics, and the mechanism of voltage-dependent activation of voltage-gated ion channels.
authors.affiliation: Department of Chemistry, University of California Irvine , Irvine, California 92697-2025, United States.
authors.forename: Mona L
authors.initials: ML
authors.lastname: Wood
authors.affiliation: Department of Chemistry, University of California Irvine , Irvine, California 92697-2025, United States.
authors.forename: J Alfredo
authors.initials: JA
authors.lastname: Freites
authors.affiliation: Department of Physiology and Biophysics, University of California Irvine , Irvine, California 92697-4560, United States.
authors.forename: Francesco
authors.initials: F
authors.lastname: Tombola
authors.affiliation: Department of Chemistry, University of California Irvine , Irvine, California 92697-2025, United States.
authors.forename: Douglas J
authors.identifier: 0000-0002-6971-9828
authors.initials: DJ
authors.lastname: Tobias
mesh_terms: D004553:Electric Conductivity; D056004:Molecular Dynamics Simulation; D000072417:Protein Domains; D051637:Shaker Superfamily of Potassium Channels / Q000737:chemistry*
chemical_list: D051637:Shaker Superfamily of Potassium Channels