title: Hydrogen-bonded water molecules in the M2 channel of the influenza A virus guide the binding preferences of ammonium-based inhibitors.
abstract: The tetrameric M2 proton channel of influenza A virus is an integral membrane protein responsible for the acidification of the viral interior. Drugs such as amantadine target the transmembrane region of wild type M2 by acting as pore blockers. However, a number of mutations affecting this domain confer drug resistance, prompting the need for alternative inhibitors. The availability of high-resolution structures of drug-bound M2, paired with computational investigations, revealed that inhibitors can bind at different sites, and provided useful insights in understanding the principles governing proton conduction. Here, we investigated by computation the energetic and geometric factors determining the relative stability of pore blockers at individual sites of different M2 strains. We found that local free energy minima along the translocation pathway of positively charged chemical species correspond to experimentally determined binding sites of inhibitors. Then, by examining the structure of water clusters hydrating each site, as well as of those displaced by binding of hydrophobic scaffolds, we predicted the binding preferences of M2 ligands. This information can be used to guide the identification of novel classes of inhibitors.
authors.affiliation: Institute for Computational Molecular Science, Temple University , SERC Building, 1925 North 12th Street, Philadelphia, Pennsylvania 19122, United States.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gianti
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Carnevale
authors.forename: William F
authors.initials: WF
authors.lastname: DeGrado
authors.forename: Michael L
authors.initials: ML
authors.lastname: Klein
authors.forename: Giacomo
authors.initials: G
authors.lastname: Fiorin
mesh_terms: D064751:Ammonium Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D009980:Influenza A virus; D020128:Inhibitory Concentration 50; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010539:Permeability; D011487:Protein Conformation; D013379:Substrate Specificity; D013816:Thermodynamics; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014867:Water / Q000378:metabolism*; D000086082:Viroporin Proteins
chemical_list: D064751:Ammonium Compounds; D014763:Viral Matrix Proteins; D014867:Water; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins