title: Water wires in atomistic models of the Hv1 proton channel.
abstract: The voltage-gated proton channel (Hv1) is homologous to the voltage-sensing domain (VSD) of voltage-gated potassium (Kv) channels but lacks a separate pore domain. The Hv1 monomer has dual functions: it gates the proton current and also serves as the proton conduction pathway. To gain insight into the structure and dynamics of the yet unresolved proton permeation pathway, we performed all-atom molecular dynamics simulations of two different Hv1 homology models in a lipid bilayer in excess water. The structure of the Kv1.2-Kv2.1 paddle-chimera VSD was used as template to generate both models, but they differ in the sequence alignment of the S4 segment. In both models, we observe a water wire that extends through the membrane, whereas the corresponding region is dry in simulations of the Kv1.2-Kv2.1 paddle-chimera. We find that the kinetic stability of the water wire is dependent upon the identity and location of the residues lining the permeation pathway, in particular, the S4 arginines. A measurement of water transport kinetics indicates that the water wire is a relatively static feature of the permeation pathway. Taken together, our results suggest that proton conduction in Hv1 may occur via Grotthuss hopping along a robust water wire, with exchange of water molecules between inner and outer ends of the permeation pathway minimized by specific water-protein interactions. This article is part of a Special Issue entitled: Membrane protein structure and function.
authors.affiliation: Department of Chemistry, University of California, Irvine, CA 92697-2025, USA.
authors.forename: Mona L
authors.initials: ML
authors.lastname: Wood
authors.forename: Eric V
authors.initials: EV
authors.lastname: Schow
authors.forename: J Alfredo
authors.initials: JA
authors.lastname: Freites
authors.forename: Stephen H
authors.initials: SH
authors.lastname: White
authors.forename: Francesco
authors.initials: F
authors.lastname: Tombola
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Tobias
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001692:Biological Transport; D006801:Humans; D007473:Ion Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051663:Kv1.2 Potassium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011487:Protein Conformation; D016415:Sequence Alignment; D051669:Shab Potassium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014867:Water / Q000378:metabolism*
chemical_list: C510235:HVCN1 protein, human; D007473:Ion Channels; D051663:Kv1.2 Potassium Channel; D051669:Shab Potassium Channels; D014867:Water