ArticleThe journal of physical chemistry. B2015
Hydrogen-bonded water molecules in the M2 channel of the influenza A virus guide the binding preferences of ammonium-based inhibitors.
Article in The journal of physical chemistry. B, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 34 citations in OpenAlex.
- Molecular biophysics and inhibition mechanism of influenza virus A M2 viroporin by adamantane-based drugs - Challenges in designing antiviral agents.Journal of structural biology: X · 2025Article
- Review
- From Acid Activation Mechanisms of Proton Conduction to Design of Inhibitors of the M2 Proton Channel of Influenza A Virus.Frontiers in molecular biosciences · 2021Review
- Influenza A M2 Inhibitor Binding Understood through Mechanisms of Excess Proton Stabilization and Channel Dynamics.Journal of the American Chemical Society · 2020Article
- Dynamical control by water at a molecular level in protein dimer association and dissociation.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- The Role of Proton Transport in Gating Current in a Voltage Gated Ion Channel, as Shown by Quantum Calculations.Sensors (Basel, Switzerland) · 2018Article
- Water is an active matrix of life for cell and molecular biology.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Slow but Steady Wins the Race: Dissimilarities among New Dual Inhibitors of the Wild-Type and the V27A Mutant M2 Channels of Influenza A Virus.Journal of medicinal chemistry · 2017Article
- Binding and Proton Blockage by Amantadine Variants of the Influenza M2Journal of medicinal chemistry · 2017Article
- Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited.ACS medicinal chemistry letters · 2017Article
- On the role of water density fluctuations in the inhibition of a proton channel.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- High-resolution structures of the M2 channel from influenza A virus reveal dynamic pathways for proton stabilization and transduction.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
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.
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