ArticleProceedings of the National Academy of Sciences of the United States of America2015
Free-energy landscape of ion-channel voltage-sensor-domain activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 70 citations in OpenAlex.
- Voltage-sensing domains: structural and functional diversity.European biophysics journal : EBJ · 2026Review
- Smoother Alchemical Transformations via Enveloping Distribution Sampling for Free-Energy Estimation.Journal of chemical theory and computation · 2026Article
- Free energy calculations in molecular modeling: from classical methods to machine learning.Journal of molecular modeling · 2026Review
- Dual mechanisms contribute to enhanced voltage dependence of an electric fish potassium channel.Biophysical journal · 2024Article
- Effective data-driven collective variables for free energy calculations from metadynamics of paths.PNAS nexus · 2024Article
- Dynamics of activation in the voltage-sensing domain of Ciona intestinalis phosphatase Ci-VSP.Nature communications · 2024Article
- Anionic omega currents from single countercharge mutants in the voltage-sensing domain of Ci-VSP.The Journal of general physiology · 2024Article
- Domain- and state-specific shape of the electric field tunes voltage sensing in voltage-gated sodium channels.Biophysical journal · 2023Article
- Modulation of the IBBA advances · 2023Article
- Mechanism of voltage gating in the voltage-sensing phosphatase Ci-VSP.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Enhanced sampling without borders: on global biasing functions and how to reweight them.Physical chemistry chemical physics : PCCP · 2022Review
- Computational methods and theory for ion channel research.Advances in physics: X · 2022Article
- Improved Hodgkin-Huxley type model for neural action potentials.European biophysics journal : EBJ · 2021Article
- The interplay of excitation and electroporation in nanosecond pulse stimulation.Bioelectrochemistry (Amsterdam, Netherlands) · 2020Review
- Polyamine blockade and binding energetics in the MthK potassium channel.The Journal of general physiology · 2020Article
- A novel theoretical framework reveals more than one voltage-sensing pathway in the lateral membrane of outer hair cells.The Journal of general physiology · 2020Article
- Microcanonical coarse-graining of the kinetic Ising model.The Journal of chemical physics · 2020Article
- Molecular Insights from Conformational Ensembles via Machine Learning.Biophysical journal · 2020Article
- Modeling the Interactions Between Sodium Channels Provides Insight Into the Negative Dominance of Certain Channel Mutations.Frontiers in physiology · 2020Article
- Roles for Countercharge in the Voltage Sensor Domain of Ion Channels.Frontiers in pharmacology · 2020Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 3 countries.
Funding
Abstract
Voltage sensor domains (VSDs) are membrane-bound protein modules that confer voltage sensitivity to membrane proteins. VSDs sense changes in the transmembrane voltage and convert the electrical signal into a conformational change called activation. Activation involves a reorganization of the membrane protein charges that is detected experimentally as transient currents. These so-called gating currents have been investigated extensively within the theoretical framework of so-called discrete-state Markov models (DMMs), whereby activation is conceptualized as a series of transitions across a discrete set of states. Historically, the interpretation of DMM transition rates in terms of transition state theory has been instrumental in shaping our view of the activation process, whose free-energy profile is currently envisioned as composed of a few local minima separated by steep barriers. Here we use atomistic level modeling and well-tempered metadynamics to calculate the configurational free energy along a single transition from first principles. We show that this transition is intrinsically multidimensional and described by a rough free-energy landscape. Remarkably, a coarse-grained description of the system, based on the use of the gating charge as reaction coordinate, reveals a smooth profile with a single barrier, consistent with phenomenological models. Our results bridge the gap between microscopic and macroscopic descriptions of activation dynamics and show that choosing the gating charge as reaction coordinate masks the topological complexity of the network of microstates participating in the transition. Importantly, full characterization of the latter is a prerequisite to rationalize modulation of this process by lipids, toxins, drugs, and genetic mutations.
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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.