Free-energy profiles for ions in the influenza M2-TMD channel

M, transmembrane domain channel (M-2-TMD) permeation properties are studied using molecular dynamics simulations of M-2-TMD (1NYJ) embedded in a lipid bilayer (DMPQ 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 NH4+ and NH4+ 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.