The M2 protein of Influenza A virus forms a homotetrameric proton channel activated by low pH. The His37-Trp41 quartet is the heart of acid activation and proton conductance, but the functional mechanism is still controversial. We carried out ab initio calculations to model the pH-dependent structures of the His37-Trp41 quartet. In our model at neutral pH, the four His37 residues are configured into a pair of dimers; in each dimer, a proton is shared between Nδ1 on one residue and Nε2 on the other, and, under the restraint of the backbone, the two imidazole rings are nearly parallel, in contrast to a perpendicular arrangement for a free imidazole–imidazolium dimer. Within each dimer the +1 charge is highly delocalized, contributing to its stabilization in a low dielectric environment. The Nδ1–H–Nε2 strong hydrogen bonds result in significantly downfield shifted Nδ1 and Nε2 chemical shifts (at 169.7 and 167.6 ppm, respectively), in good agreement with experiments. In our model at acidic pH (where the channel becomes activated), a third proton binds to an imidazole–imidazolium dimer; the imidazole rings rotate away (each by ∼55°) from each other, destroying the dimer structure. The two imidazoliums are stabilized by hydrogen bonds with water molecules and a cation–π interaction with Trp41. The Raman spectra calculated for the His37-Trp41 quartet at neutral and acidic pH are in agreement with experiments. Our calculations support an activation and conductance mechanism in which a hydronium ion from the N-terminal side transfers a proton to an imidazole–imidazolium dimer; when the Trp41 gate is open, relaying of a proton onto a water chain from the C-terminal side then allows the imidazole–imidazolium dimer to reform and be ready for the next round of proton conductance.
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