title: Proton release from the histidine-tetrad in the M2 channel of the influenza A virus.
abstract: The activity of the M2 proton channel of the influenza A virus is controlled by pH. The tautomeric state and conformation of His37, a key residue in the M2 transmembrane four-helix bundle, controls the gating of the channel. Previously, we compared the energetics and dynamics of two alternative conformations of the doubly protonated state at neutral pH, namely, a 4-fold symmetric "histidine-box" and a 2-fold symmetric "dimer-of-dimers", and proposed a multiconfiguration model for this charge state. Here, we elaborate this model by further studying configurations of the His37 tetrad in the triply protonated state and its subsequent deprotonation via quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations, starting with the aforementioned configurations, to gain information about proton release in a viral membrane environment. Interestingly, the two configurations converge under acidic pH conditions. Protons can be transferred from one charged His37 to a neighboring water cluster at the C-terminal side of the channel when the Trp41 gate is open transiently. With limited backbone expansion, the free energy barrier for proton release to the viral interior at low pH is ~6.5 kcal/mol in both models, which is much lower than at either neutral pH or for an isolated His37 cluster without a membrane environment. Our calculations also suggest that the M2 protein would seem to exclude the entrance of anions into the central channel through a special mechanism, due to the latter's potential inhibitory effect on proton conduction.
authors.affiliation: Institute for Computational Molecular Science, Temple University , 1900 North 12th Street, Philadelphia, Pennsylvania 19122-6078, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Dong
authors.forename: Giacomo
authors.initials: G
authors.lastname: Fiorin
authors.forename: William F
authors.initials: WF
authors.lastname: DeGrado
authors.forename: Michael L
authors.initials: ML
authors.lastname: Klein
mesh_terms: D006639:Histidine / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D009980:Influenza A virus / Q000737:chemistry; D015640:Ion Channel Gating; D007473:Ion Channels / Q000737:chemistry*; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011522:Protons; D011789:Quantum Theory; D013816:Thermodynamics; D014763:Viral Matrix Proteins / Q000737:chemistry*; D000086082:Viroporin Proteins
chemical_list: D006639:Histidine; D007473:Ion Channels; D011522:Protons; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins