Learning molecular traits of human pain disease via voltage-gated sodium channel structure renormalization

Learning molecular traits of human pain disease via voltage-gated sodium channel structure renormalization | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Learning molecular traits of human pain disease via voltage-gated sodium channel structure renormalization Markos Xenakis, Angelika Lampert This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6025046/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Mammalian neurophysiology vitally depends on the stable functioning of transmembrane, pore-forming voltage-sensing proteins known as voltage-gated sodium channels (NaVChs). Deciphering the principles of NaVCh spatial organization can illuminate fundamental structure-function aspects of pore-forming proteins and offer new opportunities for pharmacological treatment of associated diseases such as chronic pain. Here, we introduce a renormalization group flow paradigm permitting a formal investigation of NaVCh thermostability properties. Our procedures are solidified by deriving a q-deformed statistical mechanical entropy and validated over 121 experimentally resolved NaVCh structures of prokaryotic and eukaryotic origin. We uncover the universality of a critical inflection point regulating the thermostability of the pore domain relative to the voltage sensors, summarized in terms of a generalized Widom scaling law. A machine learning algorithm, rationalized in terms of the ’loosening’ of inertia and conductivity channel constraints, identifies pain-disease-associated mutation hotspots in the human NaV1.7 channel. Our work illustrates how first-principles-based machine learning approaches can deliver accurate insights for human pain medicine and clinicians at a reduced computational cost, while clarifying the self-organized critical nature of NaVChs. Biological sciences/Computational biology and bioinformatics/Protein structure predictions Health sciences/Neurology/Neurological disorders/Neuropathic pain Voltage-gated Sodium Channel Renormalization Criticality Human Pain Disease Machine Learning Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SIRGNaVChPain.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6025046","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":419050134,"identity":"6ce5644e-d5cb-4099-a2a9-98dff24b72c5","order_by":0,"name":"Markos Xenakis","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3klEQVRIiWNgGAWjYFACNgglwczA+ABI8/CRooXZAKSFjXgtQJYEEh830J19LPkzT8Udecl29meVX3PsZNgYmB8+uoFHi9m5tGOSM848M5zNzGN2W3ZbMtBhbMbGOfi0nGFvY/jYdphxHjMP223JbUAS6B1pAlqaPyT+O2w/j5n9WbHktnpitLAdkPjYcDhxNjODGePHbYeJ0pImOePY4eSZzTzG0ozbjvOwMRP0C5vxZ56aw7Yzzh9/+PHntmp7fvbmh4/xaUEBzDxgkljlIMD4gxTVo2AUjIJRMGIAAM9+QxbI3KSoAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-9536-4015","institution":"Uniklinik RWTH Aachen University","correspondingAuthor":true,"prefix":"","firstName":"Markos","middleName":"","lastName":"Xenakis","suffix":""},{"id":419050135,"identity":"43c7d64a-3c2b-476b-9c7e-0ca00e1be1f7","order_by":1,"name":"Angelika Lampert","email":"","orcid":"https://orcid.org/0000-0001-6319-6272","institution":"Uniklinik RWTH Aachen University","correspondingAuthor":false,"prefix":"","firstName":"Angelika","middleName":"","lastName":"Lampert","suffix":""}],"badges":[],"createdAt":"2025-02-13 17:30:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6025046/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6025046/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":79895954,"identity":"62030f7b-23a9-4c08-b2b8-8d40695c77fc","added_by":"auto","created_at":"2025-04-04 09:03:53","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":11979656,"visible":true,"origin":"","legend":"Article File","description":"","filename":"MainTextRGNaVChPain.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6025046/v1_covered_177dd21e-897e-4d03-a4cc-dacbc64f081f.pdf"},{"id":79262077,"identity":"18e7fe13-a180-48c5-a389-b7813b242af7","added_by":"auto","created_at":"2025-03-26 09:40:01","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":74756020,"visible":true,"origin":"","legend":"","description":"","filename":"SIRGNaVChPain.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6025046/v1/072d506f3f02c3604069a56b.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Learning molecular traits of human pain disease\r\nvia voltage-gated sodium channel structure\r\nrenormalization","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Voltage-gated Sodium Channel, Renormalization, Criticality, Human Pain Disease, Machine Learning","lastPublishedDoi":"10.21203/rs.3.rs-6025046/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6025046/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Mammalian neurophysiology vitally depends on the stable functioning of transmembrane, pore-forming voltage-sensing proteins known as voltage-gated sodium channels (NaVChs). Deciphering the principles of NaVCh spatial organization can illuminate fundamental structure-function aspects of pore-forming proteins and offer new opportunities for pharmacological treatment of associated diseases\r\nsuch as chronic pain. Here, we introduce a renormalization group flow paradigm permitting a formal investigation of NaVCh thermostability properties. Our procedures are solidified by deriving a q-deformed statistical mechanical entropy and validated over 121 experimentally resolved NaVCh structures of prokaryotic and eukaryotic origin. We uncover the universality of a critical inflection point regulating the thermostability of the pore domain relative to the voltage sensors,\r\nsummarized in terms of a generalized Widom scaling law. A machine learning algorithm, rationalized in terms of the ’loosening’ of inertia and conductivity channel constraints, identifies pain-disease-associated mutation hotspots in the human NaV1.7 channel. 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