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

M₂ transmembrane domain channel (M₂‐TMD) permeation properties are studied using molecular dynamics simulations of M₂‐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 M₂‐TMD tetramer are modeled for which the four His³⁷ residues, forming the selectivity filter, are net uncharged, +2 charged, or +3 charged. M₂‐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, and NH 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 Trp⁴¹ that could fully occlude the channel. Proteins 2009. © 2009 Wiley‐Liss, Inc.