title: Free-energy profiles for ions in the influenza M2-TMD channel.
abstract: M(2) transmembrane domain channel (M(2)-TMD) permeation properties are studied using molecular dynamics simulations of M(2)-TMD (1NYJ) embedded in a lipid bilayer (DMPC) with 1 mol/kg NaCl or KCl saline solution. This study allows examination of spontaneous cation and anion entry into the selectivity filter. Three titration states of the M(2)-TMD tetramer are modeled for which the four His(37) residues, forming the selectivity filter, are net uncharged, +2 charged, or +3 charged. M(2)-TMD structural properties from our simulations are compared with the properties of other models extracted from NMR and X-ray studies. During 10 ns simulations, chloride ions occasionally occupy the positively-charged selectivity filter region, and from umbrella sampling simulations, Cl(-) has a lower free-energy barrier in the selectivity-filter region than either Na(+) or NH(4) (+), and NH(4) (+) has a lower free-energy barrier than Na(+). For Na(+) and Cl(-), the free-energy barriers are less than 5 kcal/mol, suggesting that the 1NYJ conformation would probably not be exquisitely proton selective. We also point out a rotameric configuration of Trp(41) that could fully occlude the channel.
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, USA. Morad.mustafa@gmail.com
authors.forename: Morad
authors.initials: M
authors.lastname: Mustafa
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Henderson
authors.forename: David D
authors.initials: DD
authors.lastname: Busath
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D009980:Influenza A virus / Q000737:chemistry*; D007477:Ions / Q000032:analysis*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D013816:Thermodynamics; D014763:Viral Matrix Proteins / Q000737:chemistry*; D014867:Water / Q000032:analysis; D000086082:Viroporin Proteins
chemical_list: D007477:Ions; D014763:Viral Matrix Proteins; D014867:Water; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins