tetano
Editor, Senior Moderator
J Phys Chem B. 2014 Oct 29. [Epub ahead of print]
Hydrogen-bonded Water Molecules in the M2 Channel of the Influenza A Virus Guide the Binding Preferences of Ammonium-based Inhibitors.
Gianti E, Carnevale V, DeGrado WF, Klein ML, Fiorin G.
Abstract
The tetrameric M2 proton channel of the influenza A virus is an integral membrane protein responsible for the acidification of the viral interior. Drugs such as amantadine (1-adamantylamine) 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 M2 in complex with amantadine, paired with a number of computational investigations, revealed that inhibitors can bind M2 at different sites, and provides useful insights in understanding the principles governing proton conduction. Here, we computationally investigate the energetic and geometric factors determining the relative stability of M2 binders at individual sites of different strains. We observed that local free energy minima along the translocation pathway of positively charged chemical species correspond to experimentally determined binding sites of inhibitors. Then, upon examination of the structure of water molecules hydrating these sites, we were able to infer the binding preference of a ligand to a particular site. Finally, the comparison of the structure of the scaffolds of known inhibitors with clusters of water molecules displaced upon binding, revealed that the adamantane group is a significantly better partner of the wild-type M2 than of the drug-resistant mutant S31N. Our findings show that the structure of hydrogen-bonded water molecules within the M2 proton channel determines the affinity of ammonium-based inhibitors, and can be used to assist the rational design of novel M2 inhibitors.
PMID:
25353315
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/25353315
Hydrogen-bonded Water Molecules in the M2 Channel of the Influenza A Virus Guide the Binding Preferences of Ammonium-based Inhibitors.
Gianti E, Carnevale V, DeGrado WF, Klein ML, Fiorin G.
Abstract
The tetrameric M2 proton channel of the influenza A virus is an integral membrane protein responsible for the acidification of the viral interior. Drugs such as amantadine (1-adamantylamine) 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 M2 in complex with amantadine, paired with a number of computational investigations, revealed that inhibitors can bind M2 at different sites, and provides useful insights in understanding the principles governing proton conduction. Here, we computationally investigate the energetic and geometric factors determining the relative stability of M2 binders at individual sites of different strains. We observed that local free energy minima along the translocation pathway of positively charged chemical species correspond to experimentally determined binding sites of inhibitors. Then, upon examination of the structure of water molecules hydrating these sites, we were able to infer the binding preference of a ligand to a particular site. Finally, the comparison of the structure of the scaffolds of known inhibitors with clusters of water molecules displaced upon binding, revealed that the adamantane group is a significantly better partner of the wild-type M2 than of the drug-resistant mutant S31N. Our findings show that the structure of hydrogen-bonded water molecules within the M2 proton channel determines the affinity of ammonium-based inhibitors, and can be used to assist the rational design of novel M2 inhibitors.
PMID:
25353315
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/25353315