Abstract

To understand how antiviral drugs inhibit the replication of influenza A virus via the M2 ion channel, molecular dynamics simulations have been applied to the six possible protonation states of the M2 ion channel in free form and its complexes with two commercial drugs in a fully hydrated lipid bilayer. Among the six different states of free M2 tetramer, water density was present in the pore of the systems with mono-protonated, di-protonated at adjacent position, tri-protonated and tetra-protonated systems. In the presence of inhibitor, water density in the channel was considerably better reduced by rimantadine than amantadine, agreed well with the experimental IC(50) values. With the preferential position and orientation of the two drugs in all states, two mechanisms of action, where the drug binds to the opening pore and the histidine gate, were clearly explained, i.e., (i) inhibitor was detected to localize slightly closer to the histidine gate and can facilitate the orientation of His37 imidazole rings to lie in the close conformation and (ii) inhibitor acts as a blocker, binding at almost above the opening pore and interacts slightly with the three pore-lining residues, Leu26, Ala30 and Ser31. Here, the inhibitors were found to bind very weakly to the channel due to their allosteric hindrance while theirs side chains were strongly solvated.