The tetrameric M2 protein bundle of the influenza A virus is the proton channel responsible for the acidification of the viral interior, a key step in the infection cycle. Selective proton transport is achieved by successive protonation of the conserved histidine amino acids at position 37. A recent X-ray structure of the tetrameric transmembrane (TM) domain of the M2 protein (residues 22-46) resolved several water clusters (entry, bridging, and exit) in the channel lumen, which suggests possible involvement in the proton pathways to the His37 residues. To explore this hypothesis, we have carried out molecular dynamics (MD) simulations of a cation traveling towards the entry cluster and His37 side chains using classical and quantum force fields. A methyl ammonium cation diffusing through the first half of the channel towards the water clusters explores several local free-energy minima. Moreover, surrounding water molecules and peptide carbonyls are oriented to electrostatically stabilize the presence of such a positive charge in the pore. Quantum mechanical MD simulations of a proton placed in the entry cluster show that it can move to one of the acceptor His37 in a nearly barrierless fashion. Water molecules of the entry cluster, although confined in the M2 pore and restricted in their motions, can conduct protons with a rate very similar to that of bulk water.
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