{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T16:12:45Z","timestamp":1788970365686,"version":"build-2803163510"},"reference-count":82,"publisher":"American Chemical Society (ACS)","issue":"35","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit? e della Ricerca","doi-asserted-by":"publisher","award":["R18XYKRW7J"],"award-info":[{"award-number":["R18XYKRW7J"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>hERG is a voltage-gated potassium channel whose malfunction is associated with cardiac pathologies. Unlike other potassium channels, hERG exhibits a peculiarly fast C-type inactivation at the level of the selectivity filter (SF), which has complicated our understanding of its structural dynamics. Molecular Dynamics (MD) simulations offer powerful tools to probe ion channel gating, but conventional equilibrium MD simulations are often unable to capture fast transitions. Despite their potential, Dynamical Nonequilibrium MD simulations (D-NEMD) have rarely been applied to understand ion channel mechanisms. Here, we combine equilibrium MD simulations, D-NEMD simulations, and electrophysiology assays to atomistically characterize a possible pathway of hERG C-type inactivation. First, we show that the ion occupancy within the SF influences hERG propensity to spontaneously inactivate. Then, we reveal three possible major steps that underlie hERG inactivation: (i) the disruption of contacts between residues of the SF, P-helix, and S5\u2013P helix, (ii) the flipping of V625, which ultimately (iii) constricts the SF, leading to the final nonconductive state of the channel. Mutagenesis and electrophysiological recordings confirm the functional relevance of the computationally identified residues. Overall, our results demonstrate the utility of D-NEMD in investigating rapid nonequilibrium transitions in physiologically relevant complex proteins, such as ion channels, which remain a challenge for conventional equilibrium simulations and structural methods, such as X-ray crystallography and cryo-EM.<\/jats:p>","DOI":"10.1021\/jacs.6c05939","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:28:41Z","timestamp":1788218921000},"page":"37738-37750","source":"Crossref","is-referenced-by-count":0,"title":["Dynamical Nonequilibrium\nMolecular Dynamics Simulations\nReveal Atomistic Steps of C-Type Inactivation in Cardiac hERG\nChannels"],"prefix":"10.1021","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2132-0658","authenticated-orcid":true,"given":"Flavio","family":"Costa","sequence":"first","affiliation":[{"name":"Sapienza Universita\u0300 di Roma , , ,","place":["Rome, Italy, 00184"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7012-5699","authenticated-orcid":true,"given":"Carlos","family":"Bassetto","sequence":"additional","affiliation":[{"name":"UT San Antonio , , , ,","place":["San Antonio, Texas, United States, 78249"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Bezanilla","sequence":"additional","affiliation":[{"name":"The University of Chicago , , , ,","place":["Chicago, Illinois, United States, 60637"]},{"name":"The University of Chicago , , , ,","place":["Chicago, Illinois, United States, 60637"]},{"name":"Universidad de Valparaiso , , ,","place":["Valparaiso, Chile, 2284440"]},{"name":"Universidad de Valparai\u0301so , , ,","place":["Valparaiso, Chile, 2284440"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2735-6982","authenticated-orcid":true,"given":"Alberto","family":"Giacomello","sequence":"additional","affiliation":[{"name":"Sapienza Universita\u0300 di Roma , , ,","place":["Rome, Italy, 00184"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"issue":"8","key":"2026090910080415000_cit1","doi-asserted-by":"publisher","first-page":"3438","DOI":"10.1073\/pnas.91.8.3438","article-title":"A Family of Potassium Channel Genes Related to Eag\nin Drosophila and Mammals","volume":"91","author":"Warmke","year":"1994","journal-title":"Proc. Natl. Acad.\nSci. U. S. A."},{"issue":"2","key":"2026090910080415000_cit2","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/0092-8674(95)90340-2","article-title":"A Mechanistic Link\nbetween an Inherited and an Acquird Cardiac Arrthytmia: HERG Encodes\nthe IKr Potassium Channel","volume":"81","author":"Sanguinetti","year":"1995","journal-title":"Cell"},{"issue":"5220","key":"2026090910080415000_cit3","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1126\/science.7604285","article-title":"HERG, a\nHuman Inward Rectifier in the Voltage-Gated Potassium Channel Family","volume":"269","author":"Trudeau","year":"1995","journal-title":"Science"},{"issue":"3","key":"2026090910080415000_cit4","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1152\/physrev.00036.2011","article-title":"hERG K+ Channels: Structure, Function, and\nClinical Significance","volume":"92","author":"Vandenberg","year":"2012","journal-title":"Physiol. Rev."},{"issue":"5","key":"2026090910080415000_cit5","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/0092-8674(95)90358-5","article-title":"A Molecular Basis for Cardiac Arrhythmia: HERG Mutations\nCause Long QT Syndrome","volume":"80","author":"Curran","year":"1995","journal-title":"Cell"},{"issue":"6902","key":"2026090910080415000_cit6","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/nature00978","article-title":"The Voltage-Gated\nPotassium Channels and Their Relatives","volume":"419","author":"Yellen","year":"2002","journal-title":"Nature"},{"issue":"7083","key":"2026090910080415000_cit7","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/nature04710","article-title":"hERG Potassium\nChannels and Cardiac Arrhythmia","volume":"440","author":"Sanguinetti","year":"2006","journal-title":"Nature"},{"issue":"4","key":"2026090910080415000_cit8","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1017\/S0033583500003097","article-title":"The Kinetics\nof Voltage-Gated Ion Channels","volume":"27","author":"Keynes","year":"1994","journal-title":"Q. Rev. Biophys."},{"issue":"6568","key":"2026090910080415000_cit9","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1038\/379833a0","article-title":"The Inward Rectification Mechanism\nof the HERG Cardiac Potassium Channel","volume":"379","author":"Smith","year":"1996","journal-title":"Nature"},{"issue":"3","key":"2026090910080415000_cit10","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1113\/jphysiol.2001.012690","article-title":"Effects\nof premature stimulation on HERG K+ channels","volume":"537","author":"Lu","year":"2001","journal-title":"J. Physiol."},{"issue":"6","key":"2026090910080415000_cit11","doi-asserted-by":"publisher","first-page":"2795","DOI":"10.1073\/pnas.1909196117","article-title":"Selectivity\nFilter Modalities and\nRapid Inactivation of the hERG1 Channel","volume":"117","author":"Miranda","year":"2020","journal-title":"Proc.\nNatl. Acad. Sci. U. S. A."},{"issue":"5","key":"2026090910080415000_cit12","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abd6203","article-title":"Mechanism\nof C-Type Inactivation in the hERG Potassium Channel","volume":"7","author":"Li","year":"2021","journal-title":"Sci. Adv."},{"issue":"1","key":"2026090910080415000_cit13","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1021\/acs.jcim.2c01028","article-title":"Early Steps\nin C-Type Inactivation\nof the hERG Potassium Channel","volume":"63","author":"Pettini","year":"2023","journal-title":"J. Chem. Inf.\nModel."},{"issue":"1","key":"2026090910080415000_cit14","doi-asserted-by":"publisher","first-page":"7470","DOI":"10.1038\/s41467-024-51208-w","article-title":"Potassium\nDependent Structural Changes in the Selectivity Filter of HERG Potassium\nChannels","volume":"15","author":"Lau","year":"2024","journal-title":"Nat. Commun."},{"issue":"9","key":"2026090910080415000_cit15","doi-asserted-by":"publisher","first-page":"844","DOI":"10.3390\/membranes12090844","article-title":"Applications\nof Molecular Dynamics Simulation in Protein\nStudy","volume":"12","author":"Sinha","year":"2022","journal-title":"Membranes"},{"issue":"1","key":"2026090910080415000_cit16","doi-asserted-by":"publisher","first-page":"2080587","DOI":"10.1080\/23746149.2022.2080587","article-title":"Computational Methods and Theory for Ion Channel Research","volume":"7","author":"Guardiani","year":"2022","journal-title":"Adv. Phys.: X"},{"key":"2026090910080415000_cit17","doi-asserted-by":"publisher","first-page":"4097","DOI":"10.1016\/j.bpj.2025.12.024","article-title":"Conductance of a Potassium Channel\nin the Limit of Zero Membrane\nPotential","volume":"125","author":"Uriarte","year":"2026","journal-title":"Biophys. J."},{"issue":"21","key":"2026090910080415000_cit18","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2423866122","article-title":"Effective Polarization\nin Potassium Channel Simulations: Ion Conductance, Occupancy, Voltage\nResponse, and Selectivity","volume":"122","author":"Hui","year":"2025","journal-title":"Proc. Natl. Acad.\nSci. U. S. A."},{"issue":"1","key":"2026090910080415000_cit19","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1146\/annurev-biophys-062722-093258","article-title":"Free Energy\nMethods for the Description of Molecular Processes","volume":"52","author":"Chipot","year":"2023","journal-title":"Annu. Rev. Biophys."},{"issue":"16","key":"2026090910080415000_cit20","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1080\/08927022.2015.1121543","article-title":"Non-Equilibrium by\nMolecular Dynamics: A Dynamical\nApproach","volume":"42","author":"Ciccotti","year":"2016","journal-title":"Mol. Simul."},{"issue":"7","key":"2026090910080415000_cit21","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1140\/epjb\/s10051-021-00157-0","article-title":"Dynamical\nNonequilibrium Molecular Dynamics Reveals the Structural Basis for\nAllostery and Signal Propagation in Biomolecular Systems","volume":"94","author":"Oliveira","year":"2021","journal-title":"Eur. Phys. J. B"},{"issue":"6","key":"2026090910080415000_cit22","doi-asserted-by":"publisher","first-page":"1767","DOI":"10.1021\/jacsau.3c00185","article-title":"Dynamical Nonequilibrium Molecular\nDynamics Simulations Identify Allosteric Sites and Positions Associated\nwith Drug Resistance in the SARS-CoV-2 Main Protease","volume":"3","author":"Chan","year":"2023","journal-title":"JACS Au"},{"issue":"3","key":"2026090910080415000_cit23","doi-asserted-by":"publisher","first-page":"mjad021","DOI":"10.1093\/jmcb\/mjad021","article-title":"SARS-CoV-2\nSpike Variants Differ in Their Allosteric\nResponses to Linoleic Acid","volume":"15","author":"Oliveira","year":"2023","journal-title":"J. Mol. Cell Biol."},{"issue":"11","key":"2026090910080415000_cit24","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.1021\/acs.biochem.4c00161","article-title":"Signal Propagation\nin the ATPase Domain of Mycobacterium Tuberculosis DNA Gyrase from\nDynamical-Nonequilibrium Molecular Dynamics Simulations","volume":"63","author":"Kamsri","year":"2024","journal-title":"Biochemistry"},{"issue":"1","key":"2026090910080415000_cit25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/BF01011477","article-title":"Thought-Experiments\nBy Molecular\nDynamics","volume":"21","author":"Ciccotti","year":"1979","journal-title":"J. Stat. Phys."},{"issue":"3","key":"2026090910080415000_cit26","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1016\/j.cell.2017.03.048","article-title":"Cryo-EM Structure\nof the Open Human Ether-a\u0300-Go-Go\n-Related K + Channel hERG","volume":"169","author":"Wang","year":"2017","journal-title":"Cell"},{"key":"2026090910080415000_cit27","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/35102000","article-title":"Energetic\nOptimization of Ion Conduction\nRate by the K+ Selectivity Filter","volume":"414","author":"Morais-Cabral","year":"2001","journal-title":"Nature"},{"key":"2026090910080415000_cit28","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/35102009","article-title":"Chemistry\nof Ion Coordination and Hydration Revealed by a K+ Channel\u2013Fab\nComplex at 2.0 \u00c5 Resolution","volume":"414","author":"Zhou","year":"2001","journal-title":"Nature"},{"key":"2026090910080415000_cit29","doi-asserted-by":"publisher","first-page":"16829","DOI":"10.1073\/pnas.1901888116","article-title":"Structure,\nFunction, and Ion-Binding\nProperties of a K+ Channel Stabilized in the 2,4-Ion\u2013Bound\nConfiguration","volume":"116","author":"Tilegenova","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U. S.\nA."},{"key":"2026090910080415000_cit30","doi-asserted-by":"publisher","first-page":"RP104901","DOI":"10.7554\/eLife.104901.3","article-title":"Harnessing\nAlphaFold to Reveal hERG Channel Conformational State Secrets","volume":"13","author":"Ngo","year":"2025","journal-title":"Elife"},{"issue":"3","key":"2026090910080415000_cit31","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1113\/jphysiol.1996.sp021410","article-title":"Molecular\nDeterminants for Activation and Inactivation\nof HERG, a Human Inward Rectifier Potassium Channel","volume":"493","author":"Scho\u0308nherr","year":"1996","journal-title":"J. Physiol."},{"issue":"1","key":"2026090910080415000_cit32","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1038\/nsmb.1966","article-title":"Mapping\nthe Sequence of Conformational Changes Underlying Selectivity Filter\nGating in the Kv11.1 Potassium Channel","volume":"18","author":"Wang","year":"2011","journal-title":"Nat.\nStruct. Mol. Biol."},{"issue":"31","key":"2026090910080415000_cit33","doi-asserted-by":"publisher","first-page":"12181","DOI":"10.1021\/jacs.1c04802","article-title":"Ion Conduction Mechanism\nas a Fingerprint of Potassium Channels","volume":"143","author":"Domene","year":"2021","journal-title":"J. Am.\nChem. Soc."},{"key":"2026090910080415000_cit34","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.97696","article-title":"Isoleucine Gate Blocks K+ Conduction in C-Type Inactivation","volume":"13","author":"Treptow","year":"2024","journal-title":"Elife"},{"issue":"46","key":"2026090910080415000_cit35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2214151119","article-title":"Voltage-Sensor Movements in the Eag Kv Channel under\nan Applied Electric Field","volume":"119","author":"Mandala","year":"2022","journal-title":"Proc. Natl. Acad.\nSci. U. S. A."},{"issue":"7303","key":"2026090910080415000_cit36","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1038\/nature09136","article-title":"Structural Basis for\nthe Coupling\nbetween Activation and Inactivation Gates in K+ Channels","volume":"466","author":"Cuello","year":"2010","journal-title":"Nature"},{"issue":"50","key":"2026090910080415000_cit37","doi-asserted-by":"publisher","first-page":"19813","DOI":"10.1073\/pnas.0708120104","article-title":"Principles Underlying\nEnergetic Coupling along an Allosteric\nCommunication Trajectory of a Voltage-Activated K+ Channel","volume":"104","author":"Sadovsky","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"1","key":"2026090910080415000_cit38","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1073\/pnas.1319577110","article-title":"Transmembrane\nAllosteric Coupling\nof the Gates in a Potassium Channel","volume":"111","author":"Wylie","year":"2014","journal-title":"Proc. Natl.\nAcad. Sci. U. S. A."},{"issue":"33","key":"2026090910080415000_cit39","doi-asserted-by":"publisher","first-page":"8788","DOI":"10.1073\/pnas.1701330114","article-title":"Transmembrane Allosteric Energetics\nCharacterization for Strong Coupling between Proton and Potassium\nIon Binding in the KcsA Channel","volume":"114","author":"Xu","year":"2017","journal-title":"Proc. Natl.\nAcad. Sci. U. S. A."},{"issue":"5","key":"2026090910080415000_cit40","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1085\/jgp.200609644","article-title":"Cross Talk between\nActivation and Slow Inactivation\nGates of Shaker Potassium Channels","volume":"128","author":"Panyi","year":"2006","journal-title":"J. Gen.\nPhysiol."},{"issue":"12","key":"2026090910080415000_cit41","doi-asserted-by":"publisher","first-page":"6532","DOI":"10.1021\/acs.jcim.0c01179","article-title":"Conduction and Gating Properties\nof the TRAAK Channel from Molecular Dynamics Simulations with Different\nForce Fields","volume":"60","author":"Ocello","year":"2020","journal-title":"J. Chem. Inf. Model."},{"issue":"7\u20138","key":"2026090910080415000_cit42","doi-asserted-by":"publisher","DOI":"10.1080\/00268976.2024.2428350","article-title":"Dynamical Nonequilibrium Molecular\nDynamics Simulations Reveal Allosteric Networks, Signal Transduction\nMechanisms, and Sites Associated with Drug Resistance in Biomolecular\nSystems","volume":"123","author":"Balega","year":"2025","journal-title":"Mol. Phys."},{"issue":"5","key":"2026090910080415000_cit43","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1085\/jgp.20028687","article-title":"Structural and Functional\nRole of the Extracellular S5-P Linker in the HERG Potassium Channel","volume":"120","author":"Liu","year":"2002","journal-title":"J. Gen. Physiol."},{"issue":"1","key":"2026090910080415000_cit44","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1111\/j.1469-7793.1998.129bo.x","article-title":"A Mutation\nin the Pore Region of\nHERG K+ Channels Expressed in Xenopus Oocytes Reduces Rectification\nby Shifting the Voltage Dependence of Inactivation","volume":"509","author":"Zou","year":"1998","journal-title":"J. Physiol."},{"issue":"16","key":"2026090910080415000_cit45","doi-asserted-by":"publisher","first-page":"11482","DOI":"10.1074\/jbc.M113.461442","article-title":"Pore Helices\nPlay a Dynamic Role\nas Integrators of Domain Motion during Kv11.1 Channel Inactivation\nGating","volume":"288","author":"Perry","year":"2013","journal-title":"J. Biol. Chem."},{"issue":"1","key":"2026090910080415000_cit46","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1038\/s41467-023-36730-7","article-title":"Noncanonical Electromechanical Coupling\nPaths in Cardiac\nhERG Potassium Channel","volume":"14","author":"Bassetto","year":"2023","journal-title":"Nat. Commun."},{"issue":"17","key":"2026090910080415000_cit47","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.13845","article-title":"Action\nPotential Clamp Characterization of the S631A hERG Mutation Associated\nwith Short QT Syndrome","volume":"6","author":"Butler","year":"2018","journal-title":"Physiol. Rep."},{"issue":"2","key":"2026090910080415000_cit48","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/0014-5793(96)00570-4","article-title":"Time, Voltage\nand Ionic Concentration Dependence of Rectification of H- Er g Expressed\nin Xenopus Oocytes","volume":"389","author":"Wang","year":"1996","journal-title":"FEBS Lett."},{"key":"2026090910080415000_cit49","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.37558","article-title":"Single-Particle Cryo-EM Structure\nof a Voltage-Activated Potassium Channel in Lipid Nanodiscs","volume":"7","author":"Matthies","year":"2018","journal-title":"Elife"},{"issue":"4","key":"2026090910080415000_cit50","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1016\/0896-6273(95)90185-X","article-title":"Modulation of K+ Current by Frequency and External\n[K+]: A Tale of Two Inactivation Mechanisms","volume":"15","author":"Baukrowitz","year":"1995","journal-title":"Neuron"},{"issue":"6","key":"2026090910080415000_cit51","doi-asserted-by":"publisher","first-page":"3128","DOI":"10.1016\/S0006-3495(99)77464-3","article-title":"Effects\nof Outer Mouth Mutations on hERG Channel Function: A Comparison with\nSimilar Mutations in the Shaker Channel","volume":"76","author":"Fan","year":"1999","journal-title":"Biophys.\nJ."},{"issue":"1","key":"2026090910080415000_cit52","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/S0014-5793(00)01586-6","article-title":"Redox State Dependency of HERG S631C\nChannel Pharmacology:\nRelation to C-type Inactivation","volume":"474","author":"Ulens","year":"2000","journal-title":"FEBS Lett."},{"issue":"43","key":"2026090910080415000_cit53","doi-asserted-by":"publisher","first-page":"42136","DOI":"10.1074\/jbc.M212824200","article-title":"Structure\nof the HERG K+ Channel S5P Extracellular Linker","volume":"278","author":"Torres","year":"2003","journal-title":"J. Biol. Chem."},{"issue":"23","key":"2026090910080415000_cit54","doi-asserted-by":"publisher","first-page":"13357","DOI":"10.1073\/pnas.93.23.13357","article-title":"Two Functionally Distinct\nSubsites for the Binding\nof Internal Blockers to the Pore of Voltage-Activated K+ Channels","volume":"93","author":"Baukrowitz","year":"1996","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"4","key":"2026090910080415000_cit55","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1085\/jgp.200308989","article-title":"Regulation\nof Kir Channels by Intracellular pH and Extracellular K+","volume":"123","author":"Dahlmann","year":"2004","journal-title":"J. Gen. Physiol."},{"issue":"5","key":"2026090910080415000_cit56","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1016\/0896-6273(91)90277-7","article-title":"The Inactivation Gate\nof the Shaker K+ Channel Behaves\nlike an Open-Channel Blocker","volume":"7","author":"Demo","year":"1991","journal-title":"Neuron"},{"issue":"2","key":"2026090910080415000_cit57","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1113\/jphysiol.2003.046490","article-title":"Tight Coupling\nof Rubidium Conductance and Inactivation in Human KCNQ1 Potassium\nChannels","volume":"552","author":"Seebohm","year":"2003","journal-title":"J. Physiol."},{"issue":"7303","key":"2026090910080415000_cit58","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/nature09153","article-title":"Structural Mechanism\nof C-Type Inactivation in K(+) Channels","volume":"466","author":"Cuello","year":"2010","journal-title":"Nature"},{"issue":"44","key":"2026090910080415000_cit59","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abc9174","article-title":"K2P Channel C-Type Gating\nInvolves Asymmetric Selectivity Filter Order-Disorder Transitions","volume":"6","author":"Lolicato","year":"2020","journal-title":"Sci. Adv."},{"issue":"13","key":"2026090910080415000_cit60","doi-asserted-by":"publisher","first-page":"7737","DOI":"10.1021\/acs.chemrev.8b00630","article-title":"Atomistic\nSimulations of Membrane Ion Channel Conduction, Gating, and Modulation","volume":"119","author":"Flood","year":"2019","journal-title":"Chem. 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