Molecular dynamics of M2 channel protein of influenza virus

Abstract

The matrix protein 2 (M2), an integral membrane ion channel from influenza A virus, plays an essential role in the viral replication process. Due to the emergence of bird flu disease and the drug resistant strain of H5N1, the M2 channel has become an important target for anti-flu drug development. Molecular dynamics (MD) simulations of the proton-selective transmembrane M2 channel in fully hydrated phospholipid bilayer were carried out to investigate structural and dynamic properties underlying the proton transport mechanism. Molecular mechanism of protein function relies on the histidine residues of the tetrameric channel, acting like the gate for transport of a proton through membrane bilayer. For this study, all possible protonation states of the ionizable His37 were constructed to have neutral and positively charged imidazole up to +4. The six studied models correspond to non-, mono-, di- (at adjacent and diagonal subunit), tri- and tetraprotonation states. The results show that except for non- and di -protonation states at adjadcent position, the transport of water molecule across the channel was observed. In addition, the binding of amantadine and rimantadine, the channel blocker, were also assessed by MD simulation approach. MD results suggested two potential binding sites for the drugs, i.e, the residues near the extracellular mouth and inside the inner cavity of the channel pore. Moreover, rimantadine showed the blocking activity of the water transport more efficient than amantadine. This biological activity of the drugs agrees well with experimental data. For the last topic of the thesis, MD simulations of the drug resistant M2 mutants were performed. Three single mutants including S31N, A30T, and L26I were studied to gain insight into molecular mechanisms of drug binding and resistance. The results indicated that in tri-protonation state amantadine loses its function in the A30T mutant while the degree of resistance to amantadine in the L26I mutant is higher than that in the S31N mutant.