Research/Review: Structure and Linkage Disequilibrium Analysis of Adamantane Resistant Mutations in Influenza Virus M2 Proton Channel
The M2 proton channel is translated by the M gene segment of influenza viruses, and has been adopted as an attractive target
for influenza A viruses, on which a series of adamantane-based drugs act. However, recently epidemic influenza viruses have had strong
resistant effects against the adamantane-based drugs. In this paper, we combined evolutionary analyses, linkage disequilibrium as well as
molecular dynamics simulations to explore the drug resistance of the M2 proton channel, with an aim of providing an in-depth understanding
of the resistant mechanism for adamantane-based drugs. We collected 2746 coding sequences for swine, avian, and human M2
proteins. After evolutionary and linkage disequilibrium analyses, we found that the some residues in the C-terminal were associated with
the famed resistant mutation S31N. Subsequently, we constructed the 3D structures of the swine, avian as well as human M2 channel,
and performed MD simulations on these channels with a typical adamantane-based drug rimantadine. From the simulation trajectories,
we found that the resistance against the adamantane-based drugs for the M2 channel from 2009 A(H1N1) viruses was derived from the
structural allostery in the transmembrane and C-terminal regions. The helices in the transmembrane region were irregular in formation
and employed larger distances between the adjacent 2 helices, which can weaken the interactions between the adjacent 2 helices and destabilize
the helix-helix assembly, resulting in a comparatively loosely structure. The helices in the C-terminal region show a disordered
configuration, giving chances for solvent molecules to enter into the channel pore.
Keywords: Allosteric mechanism, drug resistance, influenza A virus, M2 proton channel, proton transition.
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