title: The influenza A virus M2 channel: a molecular modeling and simulation study.
abstract: The M2 protein of influenza virus forms ion channels activated by low pH which are proton permeable and play a key role in the life cycle of the virus. M2 is a 97-residue integral membrane protein containing a single transmembrane (TM) helix. M2 is present as disulfide-linked homotetramers. The TM domain of M2 has been modeled as a bundle of four parallel M2 helices. The helix bundle forms a left-handed supercoil surrounding a central pore. Residue H37 has been implicated in the mechanism of low-pH activation of the channel. Models generated with H37 in a fully deprotonated state exhibit a pore occluded by a ring of H37 side chains oriented toward the lumen of the pore. Models with H37 in a fully protonated state no longer exhibit such occlusion of the pore, as the H37 side chains adopt a more interfacial location. Extended molecular dynamics simulations with water molecules within and at the mouths of the pores support this distinction between the H37-deprotonated and H37-protonated models. These simulations suggest that only in the H37-protonated model is there a continuous column of water extending the entire length of the central pore. A mechanism for activation of M2 by low pH is presented in which the H37-deprotonated model corresponds to the "closed" form of the channel, while the H37-protonated model corresponds to the "open" form. A switch from the closed to the open form of the channel occurs if H37 is protonated midway through a simulation. The open channel is suggested to contain a wire of H-bonded water molecules which enables proton permeability.
authors.affiliation: Laboratory of Molecular Biophysics, University of Oxford, United Kingdom. mark@biop.ox.ac.uk
authors.forename: M S
authors.initials: MS
authors.lastname: Sansom
authors.forename: I D
authors.initials: ID
authors.lastname: Kerr
authors.forename: G R
authors.initials: GR
authors.lastname: Smith
authors.forename: H S
authors.initials: HS
authors.lastname: Son
mesh_terms: D003198:Computer Simulation; D009980:Influenza A virus / Q000737:chemistry*; D007473:Ion Channels / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D013698:Templates, Genetic; D014763:Viral Matrix Proteins / Q000737:chemistry*; D014867:Water / Q000737:chemistry; D000086082:Viroporin Proteins
chemical_list: D007473:Ion Channels; D014763:Viral Matrix Proteins; D014867:Water; C031540:M-protein, influenza virus; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins