title: Evaluating how rimantadines control the proton gating of the influenza A M2-proton port via allosteric binding outside of the M2-channel: MD simulations.
abstract: In order to understand how rimantadine (RMT) inhibits the proton conductance in the influenza A M2 channel via the recently proposed "allosteric mechanism", molecular dynamics simulations were applied to the M2-tetrameric protein with four RMTs bound outside the channel at the three protonation states: the 0H-closed, 1H-intermediate and 3H-open situations. In the 0H-closed state, a narrow channel with the RMT-Asp44-Trp41 H-bond network was formed, therefore the water penetration through the channel was completely blocked. The Trp41-Asp44 interaction was absent in the 1H-intermediate state, whilst the binding of RMT to Asp44 remained, which resulted in a weakened helix-helix packing, therefore the channel was partially prevented. In the 3H-open state it was found that the electrostatic repulsion from the three charged His37 residues allowed the Trp41 gate to open, permitting water to penetrate through the channel. This agreed well with the potential of the means force which is in the following order: 0H > 1H > 3H.
authors.affiliation: Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Pathumwadee
authors.initials: P
authors.lastname: Intharathep
authors.forename: Thanyada
authors.initials: T
authors.lastname: Rungrotmongkol
authors.forename: Panita
authors.initials: P
authors.lastname: Decha
authors.forename: Nadtanet
authors.initials: N
authors.lastname: Nunthaboot
authors.forename: Nopphorn
authors.initials: N
authors.lastname: Kaiyawet
authors.forename: Teerakiat
authors.initials: T
authors.lastname: Kerdcharoen
authors.forename: Pornthep
authors.initials: P
authors.lastname: Sompornpisut
authors.forename: Supot
authors.initials: S
authors.lastname: Hannongbua
mesh_terms: D000494:Allosteric Regulation; D016503:Drug Delivery Systems; D015640:Ion Channel Gating / Q000187:drug effects*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D011522:Protons; D012299:Rimantadine / Q000494:pharmacology*; D014364:Tryptophan; D014763:Viral Matrix Proteins / Q000378:metabolism*; D000086082:Viroporin Proteins
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D011506:Proteins; D011522:Protons; D012299:Rimantadine; D014364:Tryptophan; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins