The pore of the M2 channel from the influenza A virus is lined by a conserved histidine-tryptophan motif and by multiple backbone carbonyls, enclosing clusters of water molecules responsible for conducting protons and stabilizing other ions. By using molecular dynamics simulations of a small library of amine-based amphiphilic molecules (including both inactive compounds and active inhibitors), we observed sites of metastable energetic equilibrium along the pore of the channel. The relative equilibria between different sites are shifted upon the appearance of drug-resistant mutations. By applying a structural analysis of the local water network, we reproduce the high affinity sites of known inhibitors, and propose quantitative geometric requirements to be used in the search for new scaffolds.

Deconstructing the pathways of ion conduction to describe the geometry of inhibition sites of the flu's proton channel

248th National Meeting (2014)

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