title: 2D IR spectroscopy reveals the role of water in the binding of channel-blocking drugs to the influenza M2 channel.
abstract: Water is an integral part of the homotetrameric M2 proton channel of the influenza A virus, which not only assists proton conduction but could also play an important role in stabilizing channel-blocking drugs. Herein, we employ two dimensional infrared (2D IR) spectroscopy and site-specific IR probes, i.e., the amide I bands arising from isotopically labeled Ala30 and Gly34 residues, to probe how binding of either rimantadine or 7,7-spiran amine affects the water dynamics inside the M2 channel. Our results show, at neutral pH where the channel is non-conducting, that drug binding leads to a significant increase in the mobility of the channel water. A similar trend is also observed at pH 5.0 although the difference becomes smaller. Taken together, these results indicate that the channel water facilitates drug binding by increasing its entropy. Furthermore, the 2D IR spectral signatures obtained for both probes under different conditions collectively support a binding mechanism whereby amantadine-like drugs dock in the channel with their ammonium moiety pointing toward the histidine residues and interacting with a nearby water cluster, as predicted by molecular dynamics simulations. We believe these findings have important implications for designing new anti-influenza drugs.
authors: Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Ayanjeet
authors: A
authors: Ghosh
authors: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94143, USA.
authors: Jun
authors: J
authors: Wang
authors: Department of Chemistry, Syracuse University, Syracuse, New York 13244, USA.
authors: Yurii S
authors: YS
authors: Moroz
authors: Department of Chemistry, Syracuse University, Syracuse, New York 13244, USA.
authors: Ivan V
authors: IV
authors: Korendovych
authors: Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, USA.
authors: Martin
authors: M
authors: Zanni
authors: Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94143, USA.
authors: William F
authors: WF
authors: DeGrado
authors: Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Feng
authors: F
authors: Gai
authors: Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Robin M
authors: RM
authors: Hochstrasser
mesh_terms: D000547:Amantadine / Q000737:chemistry / Q000627:therapeutic use; D001665:Binding Sites; D004058:Diffusion; D006801:Humans; D009980:Influenza A virus / Q000737:chemistry*; D007251:Influenza, Human / Q000821:virology*; D056004:Molecular Dynamics Simulation; D011522:Protons; D013055:Spectrophotometry, Infrared; D014867:Water / Q000737:chemistry*
chemical_list: D011522:Protons; D014867:Water; D000547:Amantadine