title: Structural dynamics of the S4 voltage-sensor helix in lipid bilayers lacking phosphate groups.
abstract: Voltage-dependent K(+) (Kv) channels require lipid phosphates for functioning. The S4 helix, which carries the gating charges in the voltage-sensing domain (VSD), inserts into membranes while being stabilized by a protein-lipid interface in which lipid phosphates play an essential role. To examine the physical basis of the protein-lipid interface in the absence of lipid phosphates, we performed molecular dynamics (MD) simulations of a KvAP S4 variant (S4mut) in bilayers with and without lipid phosphates. We find that, in dioleoyltrimethylammoniumpropane (DOTAP) bilayers lacking lipid phosphates, the gating charges are solvated by anionic counterions and, hence, lack the bilayer support provided by phosphate-containing palmitoyloleoylglycerophosphocholine (POPC) bilayers. The result is a water-permeable bilayer with significantly smaller deformations around the peptide. Together, these results provide an explanation for the nonfunctionality of VSDs in terms of a destabilizing protein-lipid interface.
authors.affiliation: Department of Physiology and Biophysics and the Center for Biomembrane Systems, University of California, Irvine, California 92697, USA.
authors.forename: Magnus
authors.initials: M
authors.lastname: Andersson
authors.forename: J Alfredo
authors.initials: JA
authors.lastname: Freites
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Tobias
authors.forename: Stephen H
authors.initials: SH
authors.lastname: White
mesh_terms: D015640:Ion Channel Gating; D008051:Lipid Bilayers / Q000737:chemistry*; D008563:Membrane Lipids / Q000737:chemistry; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010710:Phosphates / Q000737:chemistry*; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014867:Water / Q000737:chemistry
chemical_list: D008051:Lipid Bilayers; D008563:Membrane Lipids; D010710:Phosphates; D024642:Potassium Channels, Voltage-Gated; D014867:Water