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Charybdotoxin (CTX) occludes the outer exit of the pore with Lys27 positioned in the S1 site, but the intermediate states that guide its dissociation remain unclear. Using long-timescale all-atom molecular dynamics, meta-eABF free-energy calculations, and residue-level contact analysis, we mapped the dissociation pathway of CTX from the Shaker channel. External electric fields triggered an early destabilization consistent with the voltage-dependent release of Lys27, giving rise to partially detached \u201cwobbling\u201d states. These intermediates involve coordinated axial and lateral motions of the toxin, supported by a small group of residues that maintain transient contacts with the channel vestibule. Under strong fields, K+ ions rapidly occupy S1 during these events, promoting Lys27 displacement and reducing the chance of rebinding S1. Contact patterns aligned with experimental \u03a6-values, distinguishing early- and late-breaking interactions. At the same time, the free-energy profile revealed a bound state and a wobbling intermediate separated by a modest reorganization barrier. Together, these results support a multistep dissociation mechanism shaped by voltage, K+ occupancy, and a dynamic network of residue contacts and provide an atomistic view of CTX unbinding from Shaker.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c01295","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T14:40:38Z","timestamp":1785854438000},"page":"10215-10226","source":"Crossref","is-referenced-by-count":0,"title":["Computational Insights\ninto the Dissociation Pathway\nof the Charybdotoxin\u2013Shaker Complex: Voltage Dependency and\nPotassium Modulation"],"prefix":"10.1021","volume":"66","author":[{"given":"Francisca","family":"Salas-Sepulveda","sequence":"first","affiliation":[{"name":"Universidad de Talca , , Campus Talca, 2 Norte 685 , ,","place":["Talca, Chile, 3465548"]},{"name":"Universidad de Talca , , ,","place":["Talca, Chile, 3465548"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Diaz-Franulic","sequence":"additional","affiliation":[{"name":"Universidad Andre\u0301s Bello , , ,","place":["Santiago, Chile, 8370146"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Pen\u0303a","sequence":"additional","affiliation":[{"name":"Universidad de Valparai\u0301so , , ,","place":["Valparai\u0301so, Chile, 2381850"]},{"name":"Universidad de Valparai\u0301so , , ,","place":["Valparai\u0301so, Chile, 2381850"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3482-5126","authenticated-orcid":true,"given":"David","family":"Naranjo","sequence":"additional","affiliation":[{"name":"Universidad de Valparai\u0301so , , ,","place":["Valparai\u0301so, Chile, 2381850"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2650-3565","authenticated-orcid":true,"given":"Horacio","family":"Poblete","sequence":"additional","affiliation":[{"name":"Universidad de Talca , , Campus Talca, 2 Norte 685 , ,","place":["Talca, Chile, 3465548"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"issue":"2","key":"2026083104290792100_cit1","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1038\/s41594-022-00910-8","article-title":"Towards a Structurally\nResolved Human Protein Interaction Network","volume":"30","author":"Burke","year":"2023","journal-title":"Nat. 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