ArticleProceedings of the National Academy of Sciences of the United States of America2014
Ion conduction and conformational flexibility of a bacterial voltage-gated sodium 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 55 papers.
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Who cites it
55 citing papers in PubMed.
- ARumenamides as Multitarget Ion Channel Modulators: Insights from Fenestration-Focused Docking, ADMET Profiling, and Molecular Dynamics.International journal of molecular sciences · 2026Article
- Structure-function analysis of the lithium-ion selectivity of the voltage-gated sodium channel.The Journal of general physiology · 2026Article
- Enhancement of Calcium Ion Permeation via Resonant Coupling of Ion and Terahertz Waves in Voltage Gated Calcium Channels.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Learning molecular traits of human pain disease via voltage-gated sodium channel structure renormalization.Computational and structural biotechnology journal · 2025Article
- The chemistry of electrical signaling in sodium channels from bacteria and beyond.Cell chemical biology · 2024Review
- Article
- Asymmetric contribution of a selectivity filter gate in triggering inactivation of CaV1.3 channels.The Journal of general physiology · 2024Article
- Ion channel selectivity through ion-modulated changes of selectivity filter pProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels.Journal of chemical theory and computation · 2023Article
- Mechanism of Calcium Permeation in a Glutamate Receptor Ion Channel.Journal of chemical information and modeling · 2023Article
- Computational study of ion permeation through claudin-4 paracellular channels.Annals of the New York Academy of Sciences · 2022Article
- Characterizing fenestration size in sodium channel subtypes and their accessibility to inhibitors.Biophysical journal · 2022Article
- Simulation and Machine Learning Methods for Ion-Channel Structure Determination, Mechanistic Studies and Drug Design.Frontiers in pharmacology · 2022Review
- Article
- Determinants of conductance of a bacterial voltage-gated sodium channel.Biophysical journal · 2021Article
- Electrophysiological Properties from Computations at a Single Voltage: Testing Theory with Stochastic Simulations.Entropy (Basel, Switzerland) · 2021Article
- Non-extensitivity and criticality of atomic hydropathicity around a voltage-gated sodium channel's pore: a modeling study.Journal of biological physics · 2021Article
- Nonselective cation permeation in an AMPA-type glutamate receptor.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Application of a Statistical and Linear Response Theory to Multi-Ion NaEntropy (Basel, Switzerland) · 2021Article
- Tracking Membrane Protein Dynamics in Real Time.The Journal of membrane biology · 2021Review
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
Voltage-gated Na(+) channels play an essential role in electrical signaling in the nervous system and are key pharmacological targets for a range of disorders. The recent solution of X-ray structures for the bacterial channel NavAb has provided an opportunity to study functional mechanisms at the atomic level. This channel's selectivity filter exhibits an EEEE ring sequence, characteristic of mammalian Ca(2+), not Na(+), channels. This raises the fundamentally important question: just what makes a Na(+) channel conduct Na(+) ions? Here we explore ion permeation on multimicrosecond timescales using the purpose-built Anton supercomputer. We isolate the likely protonation states of the EEEE ring and observe a striking flexibility of the filter that demonstrates the necessity for extended simulations to study conduction in this channel. We construct free energy maps to reveal complex multi-ion conduction via knock-on and "pass-by" mechanisms, involving concerted ion and glutamate side chain movements. Simulations in mixed ionic solutions reveal relative energetics for Na(+), K(+), and Ca(2+) within the pore that are consistent with the modest selectivity seen experimentally. We have observed conformational changes in the pore domain leading to asymmetrical collapses of the activation gate, similar to proposed inactivated structures of NavAb, with helix bending involving conserved residues that are critical for slow inactivation. These structural changes are shown to regulate access to fenestrations suggested to be pathways for lipophilic drugs and provide deeper insight into the molecular mechanisms connecting drug activity and slow inactivation.
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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.