title: Activation and proton transport mechanism in influenza A M2 channel.
abstract: Molecular dynamics trajectories 2 μs in length have been generated for the pH-activated, tetrameric M2 proton channel of the influenza A virus in all protonation states of the pH sensor located at the His(37) tetrad. All simulated structures are in very good agreement with high-resolution structures. Changes in the channel caused by progressive protonation of His(37) provide insight into the mechanism of proton transport. The channel is closed at both His(37) and Trp(41) sites in the singly and doubly protonated states, but it opens at Trp(41) upon further protonation. Anions access the charged His(37) and by doing so stabilize the protonated states of the channel. The narrow opening at the His(37) site, further blocked by anions, is inconsistent with the water-wire mechanism of proton transport. Instead, conformational interconversions of His(37) correlated with hydrogen bonding to water molecules indicate that these residues shuttle protons in high-protonation states. Hydrogen bonds between charged and uncharged histidines are rare. The valve at Val(27) remains on average quite narrow in all protonation states but fluctuates sufficiently to support water and proton transport. A proton transport mechanism in which the channel, depending on pH, opens at either the histidine or valine gate is only partially supported by the simulations.
authors.affiliation: NASA Ames Research Center, Moffett Field, California; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California. Electronic address: chenyu.wei@nasa.gov.
authors.forename: Chenyu
authors.initials: C
authors.lastname: Wei
authors.forename: Andrew
authors.initials: A
authors.lastname: Pohorille
mesh_terms: D001692:Biological Transport; D006639:Histidine / Q000378:metabolism; D009980:Influenza A virus; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D055550:Protein Stability; D011522:Protons; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000378:metabolism*; D014867:Water / Q000378:metabolism; D000086082:Viroporin Proteins
chemical_list: D006639:Histidine; D011522:Protons; D014763:Viral Matrix Proteins; D014867:Water; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins