ArticleThe journal of physical chemistry. B2008
A secondary gate as a mechanism for inhibition of the M2 proton channel by amantadine.
Article in The journal of physical chemistry. B, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers.
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Who cites it
73 citing papers in PubMed, 110 citations in OpenAlex.
- Adamantane-based inhibitors of the influenza A M2 proton channel: structure-based design, biological evaluation, and synthetic approaches.RSC medicinal chemistry · 2026Review
- Orientation Selection in Proton-Detected Magic-Angle Spinning Torsion Angle Experiments.The journal of physical chemistry. A · 2026Article
- Understanding and controlling pandemic influenza.Proceedings of the Japan Academy. Series B, Physical and biological sciences · 2026Review
- 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
- Revolutionizing Influenza Treatment: A Deep Dive into Targeted Drug Delivery Systems.Current pharmaceutical biotechnology · 2025Review
- Latest developments in early diagnosis and specific treatment of severe influenza infection.Journal of intensive medicine · 2024Review
- Real-time tracking of drug binding to influenza A M2 reveals a high energy barrier.Journal of structural biology: X · 2023Article
- Transient water wires mediate selective proton transport in designed channel proteins.Nature chemistry · 2023Article
- Antiviral Drugs in Influenza.International journal of environmental research and public health · 2022Review
- A quantitative paradigm for water-assisted proton transport through proteins and other confined spaces.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Effects of Cholesterol on the Partitioning of a Drug Molecule in Lipid Bilayers.The journal of physical chemistry. B · 2021Article
- 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
- Site-directed M2 proton channel inhibitors enable synergistic combination therapy for rimantadine-resistant pandemic influenza.PLoS pathogens · 2020Article
- M2 amphipathic helices facilitate pH-dependent conformational transition in influenza A virus.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Article
- All-atom virus simulations.Current opinion in virology · 2018Review
- XFEL structures of the influenza M2 proton channel: Room temperature water networks and insights into proton conduction.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Decoupled side chain and backbone dynamics for proton translocation - M2 of influenza A.Journal of molecular modeling · 2017Article
- Proton Transport Mechanism of M2 Proton Channel Studied by Laser-Induced pH Jump.Journal of the American Chemical Society · 2017Article
13 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The mechanism of inhibition of the influenza A virus M2 proton channel by the antiviral drug amantadine has been under intense investigation. The importance of a mechanistic understanding is heightened by the prevalence of amantadine-resistant mutations. To gain mechanistic insight at the molecular level, we carried out extensive molecular dynamics simulations of the tetrameric M2 proton channel in both apo and amantadine-bound forms in a lipid bilayer. The simulation of the apo form revealed that Val27 from the four M2 subunits can form a secondary gate near the channel entrance and break the water wire in the channel pore. This gate arises from physical occlusion and the elimination of hydrogen-bonding partners for water molecules. In the presence of amantadine, the secondary gate formed by Val27 and the drug molecule lying just below form an extended blockage, which breaks the water wire throughout the simulation. The location and orientation of amantadine inside of the channel pore as found in our simulation are supported by a host of experimental observations. Our study suggests a novel role for Val27 in the inhibition of the M2 proton channel by amantadine.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.