Influenza virus M2 protein: a molecular modelling study of the ion channel

The influenza A M₂ protein forms cation-selective ion channelswhich are blocked by the anti-influenza drug amantadine. A molecularmodel of the M₂ channel is presented in which a bundle of fourparallel M₂ transbilayer helices surrounds a central ion-permeablepore. Analysis of helix amphipathicity was used to aid determinationof the orientation of the helices about their long axes. Thehelices are tilted such that the N-terminal mouth of the poreis wider than the C-terminal mouth. The channel is lined byresidues V27, S31 and I42. Residues D24 and D44 are locatedat opposite mouths of the pore, which is narrowest in the vicinityof I42. Energy profiles for interaction of the channel withNa⁺, amantadine-H⁺ and cyclopentylamine-H⁺ are evaluated. Theinteraction profile for Na⁺ exhibits three minima, one at eachmouth of the pore, and one in the region of residue S31. Theamantadine-H⁺ profile exhibits a minimum close to S31 and abarrier near residue I42. This provides a molecular model foramantadine-H⁺ block of M₂ channels. The profile for cyclopentylamine-H⁺does not exhibit such a barrier. It is predicted that cyclopentyl-amine-H⁺will not act as an M₂ channel blocker.