{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:32:03Z","timestamp":1785429123287,"version":"3.56.0"},"reference-count":73,"publisher":"Rockefeller University Press","issue":"2","license":[{"start":{"date-parts":[[2023,12,21]],"date-time":"2023-12-21T00:00:00Z","timestamp":1703116800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.rupress.org\/terms\/"},{"start":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T00:00:00Z","timestamp":1718841600000},"content-version":"vor","delay-in-days":182,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["OT2OD026580"],"award-info":[{"award-number":["OT2OD026580"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM116961"],"award-info":[{"award-number":["R01GM116961"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL128537"],"award-info":[{"award-number":["R01HL128537"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL152681"],"award-info":[{"award-number":["R01HL152681"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL085844"],"award-info":[{"award-number":["R01HL085844"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["U01HL126273"],"award-info":[{"award-number":["U01HL126273"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["T32HL086350"],"award-info":[{"award-number":["T32HL086350"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["19CDA34770101"],"award-info":[{"award-number":["19CDA34770101"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["2032486"],"award-info":[{"award-number":["2032486"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009219","name":"UC Davis Department of Physiology and Membrane Biology Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009219","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["5T32GM136597-02"],"award-info":[{"award-number":["5T32GM136597-02"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Extreme Science and Engineering Discovery Environment","award":["MCB170095"],"award-info":[{"award-number":["MCB170095"]}]},{"name":"Texas Advanced Computing Center","award":["MCB20010"],"award-info":[{"award-number":["MCB20010"]}]},{"DOI":"10.13039\/100008538","name":"Pittsburgh Supercomputing Center","doi-asserted-by":"publisher","award":["PSCA17085P"],"award-info":[{"award-number":["PSCA17085P"]}],"id":[{"id":"10.13039\/100008538","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008538","name":"Pittsburgh Supercomputing Center","doi-asserted-by":"publisher","award":["MCB160089P"],"award-info":[{"award-number":["MCB160089P"]}],"id":[{"id":"10.13039\/100008538","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008538","name":"Pittsburgh Supercomputing Center","doi-asserted-by":"publisher","award":["PSCA18077P"],"award-info":[{"award-number":["PSCA18077P"]}],"id":[{"id":"10.13039\/100008538","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008538","name":"Pittsburgh Supercomputing Center","doi-asserted-by":"publisher","award":["PSCA17085P"],"award-info":[{"award-number":["PSCA17085P"]}],"id":[{"id":"10.13039\/100008538","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008538","name":"Pittsburgh Supercomputing Center","doi-asserted-by":"publisher","award":["PSCA16108P"],"award-info":[{"award-number":["PSCA16108P"]}],"id":[{"id":"10.13039\/100008538","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,2,5]]},"abstract":"<jats:p>Human voltage-gated sodium (hNaV) channels are responsible for initiating and propagating action potentials in excitable cells, and mutations have been associated with numerous cardiac and neurological disorders. hNaV1.7 channels are expressed in peripheral neurons and are promising targets for pain therapy. The tarantula venom peptide protoxin-II (PTx2) has high selectivity for hNaV1.7 and is a valuable scaffold for designing novel therapeutics to treat pain. Here, we used computational modeling to study the molecular mechanisms of the state-dependent binding of PTx2 to hNaV1.7 voltage-sensing domains (VSDs). Using Rosetta structural modeling methods, we constructed atomistic models of the hNaV1.7 VSD II and IV in the activated and deactivated states with docked PTx2. We then performed microsecond-long all-atom molecular dynamics (MD) simulations of the systems in hydrated lipid bilayers. Our simulations revealed that PTx2 binds most favorably to the deactivated VSD II and activated VSD IV. These state-specific interactions are mediated primarily by PTx2\u2019s residues R22, K26, K27, K28, and W30 with VSD and the surrounding membrane lipids. Our work revealed important protein\u2013protein and protein\u2013lipid contacts that contribute to high-affinity state-dependent toxin interaction with the channel. The workflow presented will prove useful for designing novel peptides with improved selectivity and potency for more effective and safe treatment of pain.<\/jats:p>","DOI":"10.1085\/jgp.202313368","type":"journal-article","created":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T02:20:47Z","timestamp":1701742847000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["Elucidating molecular mechanisms of protoxin-II state-specific binding to the human NaV1.7 channel"],"prefix":"10.1085","volume":"156","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7454-2924","authenticated-orcid":true,"given":"Khoa","family":"Ngo","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02vjkv261","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 1 Biophysics Graduate Group, , Davis, CA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/02vjkv261","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 2 Department of Physiology and Membrane Biology, , Davis, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8627-7208","authenticated-orcid":true,"given":"Diego","family":"Lopez Mateos","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02vjkv261","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 1 Biophysics Graduate Group, , Davis, CA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/02vjkv261","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 2 Department of Physiology and Membrane Biology, , Davis, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1684-6073","authenticated-orcid":true,"given":"Yanxiao","family":"Han","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02vjkv261","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 2 Department of Physiology and Membrane Biology, , Davis, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8684-0614","authenticated-orcid":true,"given":"Kyle C.","family":"Rouen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02vjkv261","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 1 Biophysics Graduate Group, , Davis, CA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/02vjkv261","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 2 Department of Physiology and Membrane Biology, , Davis, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3422-805X","authenticated-orcid":true,"given":"Surl-Hee","family":"Ahn","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02vjkv261","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 3 Department of Chemical Engineering, , Davis, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4437-5763","authenticated-orcid":true,"given":"Heike","family":"Wulff","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02vjkv261","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 4 Department of Pharmacology, , Davis, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6849-4885","authenticated-orcid":true,"given":"Colleen E.","family":"Clancy","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02vjkv261","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 2 Department of Physiology and Membrane Biology, , Davis, CA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/02vjkv261","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 4 Department of Pharmacology, , Davis, CA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/02vjkv261","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 5 Center for Precision Medicine and Data Science, , Davis, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2325-4834","authenticated-orcid":true,"given":"Vladimir","family":"Yarov-Yarovoy","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02vjkv261","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 2 Department of Physiology and Membrane Biology, , Davis, CA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/02vjkv261","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 6 Department of Anesthesiology and Pain Medicine, , Davis, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4767-5297","authenticated-orcid":true,"given":"Igor","family":"Vorobyov","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02vjkv261","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 2 Department of Physiology and Membrane Biology, , Davis, CA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/02vjkv261","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 4 Department of Pharmacology, , Davis, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2023,12,21]]},"reference":[{"key":"2024122101021772900_bib1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1085\/jgp.201511492","article-title":"The hitchhiker\u2019s guide to the voltage-gated sodium channel galaxy","volume":"147","author":"Ahern","year":"2016","journal-title":"J. Gen. Physiol."},{"key":"2024122101021772900_bib2","doi-asserted-by":"publisher","first-page":"5340","DOI":"10.1021\/acs.jcim.9b00968","article-title":"Ranking of ligand binding kinetics using a weighted ensemble approach and comparison with a multiscale milestoning approach","volume":"60","author":"Ahn","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"2024122101021772900_bib3","doi-asserted-by":"publisher","first-page":"7938","DOI":"10.1021\/acs.jctc.1c00770","article-title":"Gaussian-accelerated molecular dynamics with the weighted ensemble method: A hybrid method improves thermodynamic and kinetic sampling","volume":"17","author":"Ahn","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"2024122101021772900_bib4","doi-asserted-by":"publisher","first-page":"aac5464","DOI":"10.1126\/science.aac5464","article-title":"Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist","volume":"350","author":"Ahuja","year":"2015","journal-title":"Science"},{"key":"2024122101021772900_bib5","doi-asserted-by":"publisher","first-page":"2042","DOI":"10.1016\/j.bpj.2020.03.006","article-title":"Protein structure prediction and design in a biologically realistic implicit membrane","volume":"118","author":"Alford","year":"2020","journal-title":"Biophys. J."},{"key":"2024122101021772900_bib6","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1080\/19336950.2019.1666455","article-title":"Voltage gated sodium channels in cancer and their potential mechanisms of action","volume":"13","author":"Angus","year":"2019","journal-title":"Channels"},{"key":"2024122101021772900_bib7","doi-asserted-by":"publisher","first-page":"58","DOI":"10.3389\/fphar.2019.00058","article-title":"Venom-derived peptide modulators of cation-selective channels: Friend, foe or frenemy","volume":"10","author":"Bajaj","year":"2019","journal-title":"Front. Pharmacol."},{"key":"2024122101021772900_bib8","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1152\/physrev.00052.2017","article-title":"The role of voltage-gated sodium channels in pain signaling","volume":"99","author":"Bennett","year":"2019","journal-title":"Physiol. Rev."},{"key":"2024122101021772900_bib9","doi-asserted-by":"publisher","first-page":"3257","DOI":"10.1021\/ct300400x","article-title":"Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone \u03c6, \u03c8 and side-chain \u03c7(1) and \u03c7(2) dihedral angles","volume":"8","author":"Best","year":"2012","journal-title":"J. Chem. Theory Comput."},{"key":"2024122101021772900_bib10","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.3390\/ph14121303","article-title":"Peptide inhibitors of Kv1. 5: An option for the treatment of atrial fibrillation","volume":"14","author":"Borrego","year":"2021","journal-title":"Pharmaceuticals"},{"key":"2024122101021772900_bib11","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1085\/jgp.201310998","article-title":"Domain IV voltage-sensor movement is both sufficient and rate limiting for fast inactivation in sodium channels","volume":"142","author":"Capes","year":"2013","journal-title":"J. Gen. Physiol."},{"key":"2024122101021772900_bib12","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1085\/jgp.20028679","article-title":"Tracking voltage-dependent conformational changes in skeletal muscle sodium channel during activation","volume":"120","author":"Chanda","year":"2002","journal-title":"J. Gen. Physiol."},{"key":"2024122101021772900_bib13","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1085\/jgp.200308971","article-title":"Coupling interactions between voltage sensors of the sodium channel as revealed by site-specific measurements","volume":"123","author":"Chanda","year":"2004","journal-title":"J. Gen. Physiol."},{"key":"2024122101021772900_bib14","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.1021\/acs.jctc.1c01049","article-title":"A companion guide to the string method with swarms of trajectories: Characterization, performance, and pitfalls","volume":"18","author":"Chen","year":"2022","journal-title":"J. Chem. Theory Comput."},{"key":"2024122101021772900_bib15","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1021\/acsptsci.9b00079","article-title":"Venom peptides with dual modulatory activity on the voltage-gated sodium channel NaV1. 1 provide novel leads for development of antiepileptic drugs","volume":"3","author":"Chow","year":"2019","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"2024122101021772900_bib16","doi-asserted-by":"publisher","first-page":"1278","DOI":"10.1126\/science.aaw8645","article-title":"Sodium channels caught in the act","volume":"363","author":"Chowdhury","year":"2019","journal-title":"Science"},{"key":"2024122101021772900_bib17","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav8573","article-title":"Structural basis of \u03b1-scorpion toxin action on Nav channels","volume":"363","author":"Clairfeuille","year":"2019","journal-title":"Science"},{"key":"2024122101021772900_bib18","doi-asserted-by":"publisher","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle mesh Ewald: An N\u00b7log(N) method for Ewald sums in large systems","volume":"98","author":"Darden","year":"1993","journal-title":"J. Chem. Phys."},{"key":"2024122101021772900_bib19","doi-asserted-by":"publisher","first-page":"7093","DOI":"10.1021\/jm501981g","article-title":"Voltage-gated sodium channels: Structure, function, Pharmacology, and clinical indications","volume":"58","author":"de Lera Ruiz","year":"2015","journal-title":"J. Med. Chem."},{"key":"2024122101021772900_bib20","doi-asserted-by":"publisher","first-page":"362","DOI":"10.3390\/molecules22030362","article-title":"Molecular simulations of disulfide-rich venom peptides with ion channels and membranes","volume":"22","author":"Deplazes","year":"2017","journal-title":"Molecules"},{"key":"2024122101021772900_bib21","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/nrn3404","article-title":"The Na(V)1.7 sodium channel: From molecule to man","volume":"14","author":"Dib-Hajj","year":"2013","journal-title":"Nat. Rev. Neurosci."},{"key":"2024122101021772900_bib22","doi-asserted-by":"publisher","first-page":"3603","DOI":"10.1172\/JCI33297","article-title":"Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders","volume":"117","author":"Drenth","year":"2007","journal-title":"J. Clin. Invest."},{"key":"2024122101021772900_bib23","doi-asserted-by":"publisher","first-page":"5722","DOI":"10.1021\/jacs.6b02682","article-title":"Interaction entropy: A new paradigm for highly efficient and reliable computation of protein-ligand binding free energy","volume":"138","author":"Duan","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"2024122101021772900_bib24","doi-asserted-by":"publisher","first-page":"7737","DOI":"10.1021\/acs.chemrev.8b00630","article-title":"Atomistic simulations of membrane ion channel conduction, gating, and modulation","volume":"119","author":"Flood","year":"2019","journal-title":"Chem. Rev."},{"key":"2024122101021772900_bib25","doi-asserted-by":"publisher","first-page":"16","DOI":"10.3941\/jrcr.v8i8.2194","article-title":"Congenital indifference to pain: An illustrated case report and literature review","volume":"8","author":"Golshani","year":"2014","journal-title":"J. Radiol. Case Rep."},{"key":"2024122101021772900_bib26","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/s0022-2836(03)00670-3","article-title":"Protein-protein docking with simultaneous optimization of rigid-body displacement and side-chain conformations","volume":"331","author":"Gray","year":"2003","journal-title":"J. Mol. Biol."},{"key":"2024122101021772900_bib27","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1007\/978-1-59745-177-2_4","article-title":"Comparison of protein force fields for molecular dynamics simulations","volume":"443","author":"Guvench","year":"2008","journal-title":"Methods Mol. Biol."},{"key":"2024122101021772900_bib28","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2215916120","article-title":"Elucidation of a dynamic interplay between a beta-2 adrenergic receptor, its agonist, and stimulatory G protein","volume":"120","author":"Han","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2024122101021772900_bib29","doi-asserted-by":"publisher","first-page":"17049","DOI":"10.1074\/jbc.M116.729095","article-title":"Interaction of tarantula venom peptide ProTx-II with lipid membranes is a prerequisite for its inhibition of human voltage-gated sodium channel NaV1.7","volume":"291","author":"Henriques","year":"2016","journal-title":"J. Biol. Chem."},{"key":"2024122101021772900_bib30","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1007\/s11916-017-0606-z","article-title":"Medication overuse in chronic pain","volume":"21","author":"Hsu","year":"2017","journal-title":"Curr. Pain Headache Rep."},{"key":"2024122101021772900_bib31","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.1002\/jcc.23354","article-title":"CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data","volume":"34","author":"Huang","year":"2013","journal-title":"J. Comput. Chem."},{"key":"2024122101021772900_bib32","doi-asserted-by":"publisher","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: A web-based graphical user interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"key":"2024122101021772900_bib33","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"2024122101021772900_bib34","doi-asserted-by":"publisher","first-page":"193","DOI":"10.3390\/toxins13030193","article-title":"Potency-enhancing mutations of gating modifier toxins for the voltage-gated sodium channelchannel NaV1.7 can Be predicted using accurate free-energy calculations","volume":"13","author":"Katz","year":"2021","journal-title":"Toxins"},{"key":"2024122101021772900_bib35","doi-asserted-by":"publisher","first-page":"7830","DOI":"10.1021\/jp101759q","article-title":"Update of the CHARMM all-atom additive force field for lipids: Validation on six lipid types","volume":"114","author":"Klauda","year":"2010","journal-title":"J. Phys. Chem. B"},{"key":"2024122101021772900_bib36","doi-asserted-by":"publisher","first-page":"2395","DOI":"10.1021\/cr00023a004","article-title":"Free energy calculations: Applications to chemical and biochemical phenomena","volume":"93","author":"Kollman","year":"1993","journal-title":"Chem. Rev."},{"key":"2024122101021772900_bib37","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1021\/ar000033j","article-title":"Calculating structures and free energies of complex molecules: Combining molecular mechanics and continuum models","volume":"33","author":"Kollman","year":"2000","journal-title":"Acc. Chem. Res."},{"key":"2024122101021772900_bib38","doi-asserted-by":"publisher","first-page":"D524","DOI":"10.1093\/nar\/gks1169","article-title":"PDBTM: Protein Data Bank of transmembrane proteins after 8 years","volume":"41","author":"Kozma","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"2024122101021772900_bib39","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1021\/acs.jcim.8b00248","article-title":"Accurate and efficient calculation of protein-protein binding free energy-interaction entropy with residue type-specific dielectric constants","volume":"59","author":"Liu","year":"2019","journal-title":"J. Chem. Inf. Model."},{"key":"2024122101021772900_bib40","doi-asserted-by":"publisher","first-page":"11035","DOI":"10.1063\/1.1622376","article-title":"A Poisson\u2013Boltzmann dynamics method with nonperiodic boundary condition","volume":"119","author":"Lu","year":"2003","journal-title":"J. Chem. Phys."},{"key":"2024122101021772900_bib41","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1038\/nmeth0809-551","article-title":"Sub-angstrom accuracy in protein loop reconstruction by robotics-inspired conformational sampling","volume":"6","author":"Mandell","year":"2009","journal-title":"Nat. Methods"},{"key":"2024122101021772900_bib42","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1002\/prot.26474","article-title":"Structural modeling of peptide toxin-ion channel interactions using RosettaDock","volume":"91","author":"Mateos","year":"2023","journal-title":"Proteins"},{"key":"2024122101021772900_bib61","doi-asserted-by":"publisher","first-page":"3314","DOI":"10.1021\/ct300418h","article-title":"MMPBSA.py: An efficient program for end-state free energy calculations","volume":"8","author":"Miller","year":"2012","journal-title":"J. Chem. Theory Comput."},{"key":"2024122101021772900_bib43","doi-asserted-by":"publisher","first-page":"12706","DOI":"10.1073\/pnas.0404915101","article-title":"Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain","volume":"101","author":"Nassar","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2024122101021772900_bib44","doi-asserted-by":"publisher","first-page":"842032","DOI":"10.3389\/fphar.2022.842032","article-title":"Towards structure-guided development of pain therapeutics targeting voltage-gated sodium channels","volume":"13","author":"Nguyen","year":"2022","journal-title":"Front. Pharmacol."},{"key":"2024122101021772900_bib45","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.81727","article-title":"Computational design of peptides to target NaV1.7 channel with high potency and selectivity for the treatment of pain","volume":"11","author":"Nguyen","year":"2022","journal-title":"Elife"},{"key":"2024122101021772900_bib46","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1002\/pro.3943","article-title":"UCSF ChimeraX: Structure visualization for researchers, educators, and developers","volume":"30","author":"Pettersen","year":"2021","journal-title":"Protein Sci. Publ. Protein Soc."},{"key":"2024122101021772900_bib47","doi-asserted-by":"publisher","first-page":"3084","DOI":"10.1021\/ct400341p","article-title":"PTRAJ and CPPTRAJ: Software for processing and analysis of molecular dynamics trajectory data","volume":"9","author":"Roe","year":"2013","journal-title":"J. Chem. Theory Comput."},{"key":"2024122101021772900_bib48","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/S0076-6879(04)83004-0","article-title":"Protein structure prediction using Rosetta","volume":"383","author":"Rohl","year":"2004","journal-title":"Methods Enzymol."},{"key":"2024122101021772900_bib49","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/0021-9991(77)90098-5","article-title":"Numerical integration of the cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes","volume":"23","author":"Ryckaert","year":"1977","journal-title":"J. Comput. Phys."},{"key":"2024122101021772900_bib50","doi-asserted-by":"publisher","first-page":"W443","DOI":"10.1093\/nar\/gkv315","article-title":"PLIP: Fully automated protein-ligand interaction profiler","volume":"43","author":"Salentin","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"2024122101021772900_bib51","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1002\/wcms.1121","article-title":"An overview of the Amber biomolecular simulation package","volume":"3","author":"Salomon-Ferrer","year":"2013","journal-title":"Wiley Interdiscip. Rev. Comput. Mol. Sci."},{"key":"2024122101021772900_bib52","doi-asserted-by":"publisher","first-page":"1476","DOI":"10.1124\/mol.108.047670","article-title":"ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors","volume":"74","author":"Schmalhofer","year":"2008","journal-title":"Mol. Pharmacol."},{"key":"2024122101021772900_bib53","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1126\/science.aaw2493","article-title":"Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins","volume":"363","author":"Shen","year":"2019","journal-title":"Science"},{"key":"2024122101021772900_bib54","doi-asserted-by":"publisher","first-page":"2454","DOI":"10.1021\/acs.jcim.1c00410","article-title":"Improving the performance of MM\/PBSA in protein-protein interactions via the screening electrostatic energy","volume":"61","author":"Sheng","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"2024122101021772900_bib55","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1007\/s10822-016-9977-1","article-title":"Lessons learned from comparing molecular dynamics engines on the SAMPL5 dataset","volume":"31","author":"Shirts","year":"2017","journal-title":"J. Comput. Aided Mol. Des."},{"key":"2024122101021772900_bib56","doi-asserted-by":"publisher","first-page":"1735","DOI":"10.1016\/j.str.2013.08.005","article-title":"High-resolution comparative modeling with RosettaCM","volume":"21","author":"Song","year":"2013","journal-title":"Structure"},{"key":"2024122101021772900_bib57","doi-asserted-by":"publisher","first-page":"46","DOI":"10.3389\/fmolb.2016.00046","article-title":"dMM-PBSA: A new HADDOCK scoring function for protein-peptide docking","volume":"3","author":"Spiliotopoulos","year":"2016","journal-title":"Front. Mol. Biosci."},{"key":"2024122101021772900_bib58","doi-asserted-by":"publisher","first-page":"9401","DOI":"10.1021\/ja981844+","article-title":"Continuum solvent studies of the stability of DNA, RNA, and Phosphoramidate\u2212DNA helices","volume":"120","author":"Srinivasan","year":"1998","journal-title":"J. Am. Chem. Soc."},{"key":"2024122101021772900_bib59","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0063090","article-title":"Improvements to robotics-inspired conformational sampling in rosetta","volume":"8","author":"Stein","year":"2013","journal-title":"PLoS One"},{"key":"2024122101021772900_bib60","doi-asserted-by":"publisher","first-page":"14450","DOI":"10.1039\/C7CP07623A","article-title":"Assessing the performance of MM\/PBSA and MM\/GBSA methods. 7. Entropy effects on the performance of end-point binding free energy calculation approaches","volume":"20","author":"Sun","year":"2018","journal-title":"Phys. Chem. Chem. Phys."},{"key":"2024122101021772900_bib62","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1021\/acs.bioconjchem.9b00744","article-title":"Enzymatic ligation of a pore blocker toxin and a gating modifier toxin: Creating double-knotted peptides with improved sodium channelchannel NaV1.7 inhibition","volume":"31","author":"Tran","year":"2020","journal-title":"Bioconjug. Chem."},{"key":"2024122101021772900_bib63","doi-asserted-by":"publisher","first-page":"154109","DOI":"10.1063\/5.0021399","article-title":"Peptide Gaussian accelerated molecular dynamics (Pep-GaMD): Enhanced sampling and free energy and kinetics calculations of peptide binding","volume":"153","author":"Wang","year":"2020","journal-title":"J. Chem. Phys."},{"key":"2024122101021772900_bib64","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1016\/j.jmb.2007.07.050","article-title":"Protein-protein docking with backbone flexibility","volume":"373","author":"Wang","year":"2007","journal-title":"J. Mol. Biol."},{"key":"2024122101021772900_bib65","doi-asserted-by":"publisher","first-page":"2436","DOI":"10.1002\/jcc.24467","article-title":"Calculating protein-ligand binding affinities with MMPBSA: Method and error analysis","volume":"37","author":"Wang","year":"2016","journal-title":"J. Comput. Chem."},{"key":"2024122101021772900_bib66","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.17219","article-title":"Automated structure refinement of macromolecular assemblies from cryo-EM maps using Rosetta","volume":"5","author":"Wang","year":"2016","journal-title":"Elife"},{"key":"2024122101021772900_bib67","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/s0304-4157(98)00021-5","article-title":"Hydrophobic interactions of peptides with membrane interfaces","volume":"1376","author":"White","year":"1998","journal-title":"Biochim. Biophys. Acta"},{"key":"2024122101021772900_bib68","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1038\/s41573-019-0013-8","article-title":"Antibodies and venom peptides: New modalities for ion channels","volume":"18","author":"Wulff","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"2024122101021772900_bib69","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1124\/mol.110.066332","article-title":"The tarantula toxins ProTx-II and huwentoxin-IV differentially interact with human Nav1.7 voltage sensors to inhibit channel activation and inactivation","volume":"78","author":"Xiao","year":"2010","journal-title":"Mol. Pharmacol."},{"key":"2024122101021772900_bib70","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1016\/j.cell.2018.12.018","article-title":"Structural basis of Nav1.7 inhibition by a gating-modifier spider toxin","volume":"176","author":"Xu","year":"2019","journal-title":"Cell"},{"key":"2024122101021772900_bib71","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000019898","article-title":"A review of the mechanism of the central analgesic effect of lidocaine","volume":"99","author":"Yang","year":"2020","journal-title":"Medicine"},{"key":"2024122101021772900_bib72","doi-asserted-by":"publisher","first-page":"729","DOI":"10.3390\/ijms20030729","article-title":"BmK AEP, an anti-epileptic peptide distinctly affects the gating of brain subtypes of voltage-gated sodium channels","volume":"20","author":"Zhang","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"2024122101021772900_bib73","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1146\/annurev-biophys-070816-033834","article-title":"Weighted ensemble simulation: Review of methodology, applications, and software","volume":"46","author":"Zuckerman","year":"2017","journal-title":"Annu. Rev. Biophys."}],"container-title":["Journal of General Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jgp\/article-pdf\/doi\/10.1085\/jgp.202313368\/1922157\/jgp_202313368.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jgp\/article-pdf\/doi\/10.1085\/jgp.202313368\/1922157\/jgp_202313368.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T20:02:27Z","timestamp":1734724947000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jgp\/article\/156\/2\/e202313368\/276472\/Elucidating-molecular-mechanisms-of-protoxin-II"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,21]]},"references-count":73,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2024,2,5]]}},"URL":"https:\/\/doi.org\/10.1085\/jgp.202313368","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.02.27.530360","asserted-by":"object"}]},"ISSN":["0022-1295","1540-7748"],"issn-type":[{"value":"0022-1295","type":"print"},{"value":"1540-7748","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,21]]},"article-number":"e202313368"}}