title: Computer simulation of ion channel gating: the M(2) channel of influenza A virus in a lipid bilayer.
abstract: The transmembrane fragment of the influenza virus M(2) protein forms a homotetrameric channel that transports protons. In this paper, we use molecular dynamics simulations to help elucidate the mechanism of channel gating by four histidines that occlude the channel lumen in the closed state. We test two competing hypotheses. In the "shuttle" mechanism, the delta nitrogen atom on the extracellular side of one histidine is protonated by the incoming proton, and, subsequently, the proton on the epsilon nitrogen atom is released on the opposite side. In the "water-wire" mechanism, the gate opens because of electrostatic repulsion between four simultaneously biprotonated histidines. This allows for proton transport along the water wire that penetrates the gate. For each system, composed of the channel embedded in a hydrated phospholipid bilayer, a 1.3-ns trajectory was obtained. It is found that the states involved in the shuttle mechanism, which contain either single-protonated histidines or a mixture of single-protonated histidines plus one biprotonated residue, are stable during the simulations. Furthermore, the orientations and dynamics of water molecules near the gate are conducive to proton transfer. In contrast, the fully biprotonated state is not stable. Additional simulations show that if only two histidines are biprotonated, the channel deforms but the gate remains closed. These results support the shuttle mechanism but not the gate-opening mechanism of proton gating in M(2).
authors.affiliation: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94143, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Schweighofer
authors.forename: A
authors.initials: A
authors.lastname: Pohorille
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D003198:Computer Simulation; D004134:Dimyristoylphosphatidylcholine; D015640:Ion Channel Gating; D007473:Ion Channels / Q000737:chemistry / Q000502:physiology; D008051:Lipid Bilayers / Q000737:chemistry*; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D055672:Static Electricity; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000502:physiology*
chemical_list: D007473:Ion Channels; D008051:Lipid Bilayers; C031540:M-protein, influenza virus; D046911:Macromolecular Substances; D014763:Viral Matrix Proteins; D004134:Dimyristoylphosphatidylcholine