ArticleProceedings of the National Academy of Sciences of the United States of America2014
Multiscale simulation reveals a multifaceted mechanism of proton permeation through the influenza A M2 proton channel.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 94 citations in OpenAlex.
- Structural Transition from Closed to Open for the Influenza A M2 Proton Channel as Observed by Proton-Detected Solid-State NMR.Journal of the American Chemical Society · 2025Article
- 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
- The interplay of polarizable water and protein in the activation of the M2 channel.Frontiers in pharmacology · 2025Article
- Activation of the Influenza B M2 Proton Channel (BM2).Biochemistry · 2024Article
- Quantitative insights into the mechanism of proton conduction and selectivity for the human voltage-gated proton channel Hv1.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Activation of the influenza B M2 proton channel (BM2).bioRxiv : the preprint server for biology · 2024Article
- QM/CG-MM: Systematic Embedding of Quantum Mechanical Systems in a Coarse-Grained Environment with Accurate Electrostatics.The journal of physical chemistry. A · 2024Article
- Molecular Dynamics Simulation of Complex Reactivity with the Rapid Approach for Proton Transport and Other Reactions (RAPTOR) Software Package.The journal of physical chemistry. B · 2024Article
- The role of conformational change and key glutamic acid residues in the ClC-ec1 antiporter.Biophysical journal · 2023Article
- Molecular origins of asymmetric proton conduction in the influenza M2 channel.Biophysical journal · 2023Article
- Generalized Transition State Theory Treatment of Water-Assisted Proton Transport Processes in Proteins.The journal of physical chemistry. B · 2022Article
- Many roads lead to CASM: Diverse stimuli of noncanonical autophagy share a unifying molecular mechanism.Science advances · 2022Review
- Ion permeation, selectivity, and electronic polarization in fluoride channels.Biophysical journal · 2022Article
- Multiscale Simulation of an Influenza A M2 Channel Mutant Reveals Key Features of Its Markedly Different Proton Transport Behavior.Journal of the American Chemical Society · 2022Article
- Spiers Memorial Lecture: Analysis andFaraday discussions · 2021Article
- 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
- Water orientation and dynamics in the closed and open influenza B virus M2 proton channels.Communications biology · 2021Article
- Influenza A M2 Inhibitor Binding Understood through Mechanisms of Excess Proton Stabilization and Channel Dynamics.Journal of the American Chemical Society · 2020Article
- Multiscale Simulation Reveals Passive Proton Transport Through SERCA on the Microsecond Timescale.Biophysical journal · 2020Article
- Understanding and Tracking the Excess Proton in Ab Initio Simulations; Insights from IR Spectra.The journal of physical chemistry. B · 2020Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The influenza A virus M2 channel (AM2) is crucial in the viral life cycle. Despite many previous experimental and computational studies, the mechanism of the activating process in which proton permeation acidifies the virion to release the viral RNA and core proteins is not well understood. Herein the AM2 proton permeation process has been systematically characterized using multiscale computer simulations, including quantum, classical, and reactive molecular dynamics methods. We report, to our knowledge, the first complete free-energy profiles for proton transport through the entire AM2 transmembrane domain at various pH values, including explicit treatment of excess proton charge delocalization and shuttling through the His37 tetrad. The free-energy profiles reveal that the excess proton must overcome a large free-energy barrier to diffuse to the His37 tetrad, where it is stabilized in a deep minimum reflecting the delocalization of the excess charge among the histidines and the cost of shuttling the proton past them. At lower pH values the His37 tetrad has a larger total charge that increases the channel width, hydration, and solvent dynamics, in agreement with recent 2D-IR spectroscopic studies. The proton transport barrier becomes smaller, despite the increased charge repulsion, due to backbone expansion and the more dynamic pore water molecules. The calculated conductances are in quantitative agreement with recent experimental measurements. In addition, the free-energy profiles and conductances for proton transport in several mutants provide insights for explaining our findings and those of previous experimental mutagenesis studies.
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