Multi-Tool Computational Analysis of Mutational Tolerance at Critical Human BEST1 Bestrophin-1 Residues..."

Multi-Tool Computational Analysis of Mutational Tolerance at Critical Human BEST1 Bestrophin-1 Residues..." | 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 Research Article Multi-Tool Computational Analysis of Mutational Tolerance at Critical Human BEST1 Bestrophin-1 Residues..." Zeemal Fatima Nawaz This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9389974/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 Abstract Background: Bestrophinopathies, including Best Vitelliform Macular Dystrophy (BVMD), are caused by mutations in the BEST1 gene. Despite its clinical importance, the mutational tolerance of many critical residues remain poorly understood, particularly in South Asian populations where clinical data is often underrepresented. Methods: This study utilizes an integrated in silico framework to evaluate the impact of amino acid substitutions on the Bestrophin-1 protein (PDB: 6N28). We employed a six-component computational pipeline—including PolyPhen-2 for functional impact, and DynaMut2 and mCSM for protein stability—to analyze high-risk variants. Structural models were validated using SAVES v6.1 (ERRAT and Ramachandran plots). Results: Our analysis achieved 100% concordance with known human clinical variants (e.g., W93C, P297S) obtained from ClinVar and HGMD. We identified specific mutational hotspots at critical residues where amino acid substitutions significantly disrupt the protein's three-dimensional discordance and stability. The structural validation scores (ERRAT: 88.162) confirm the high reliability of the predicted deleterious effects. General Biochemistry BEST1 Bestrophinopathy Mutational Tolerance In Silico Analysis Protein Stability Computational Biology. Full Text Additional Declarations The authors declare no competing interests. Supplementary Files BEST1HumanBioRxiv1.pdf BEST1 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-9389974","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":621503286,"identity":"671315ca-21ad-414f-943e-dd23342e2f8a","order_by":0,"name":"Zeemal Fatima Nawaz","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIie3PvQrCMBDA8ZSDuARdU6r4CoGCo30WCWRKcHASBwWhLoJvExyVDl18gIiLVXAVEb9wsXVzaesmmP+QW+4HF4Rstp8OUGebDlItTyqjPcsILk/I8kCzWUiak2i5W8/bATNc9C+yXccIkp3JIc5UcF+tODAjxKaheXoY9n2ZQwDJlqdCwMxIsXE1pIRgL4/g2vH2VOGQMNO99lw9LCaESgwqjChbLYRz0lExofTgp4fFzI1H3HN0TDAU/KU548lZhYOgGqHO6aEHQa0yTvZ55CMg77fsepZz/2bbZrPZ/qYX7xVD+UXPGWEAAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0004-6484-1199","institution":"UNIVERSITY OF NAROWAL","correspondingAuthor":true,"prefix":"","firstName":"Zeemal","middleName":"Fatima","lastName":"Nawaz","suffix":""}],"badges":[],"createdAt":"2026-04-11 18:16:48","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9389974/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9389974/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106960674,"identity":"7d3a45ac-ac07-435c-830a-2deceaadc22c","added_by":"auto","created_at":"2026-04-15 09:22:32","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":165970,"visible":true,"origin":"","legend":"","description":"","filename":"BEST1HumanBioRxiv1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9389974/v1_covered_e1993faf-a62e-4368-87c1-e2a8e9a9497e.pdf"},{"id":106843060,"identity":"bc24352d-c610-4a2a-849f-b535c16019c0","added_by":"auto","created_at":"2026-04-14 03:59:24","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":46584,"visible":true,"origin":"","legend":"\u003cp\u003eBEST1\u003c/p\u003e","description":"","filename":"BEST1HumanBioRxiv1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9389974/v1/fe17ffc2fac4dc6b301a72d7.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cem\u003eMulti-Tool Computational Analysis of Mutational Tolerance at Critical Human BEST1 Bestrophin-1 Residues...\"\u003c/em\u003e\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"UNIVERSITY OF NAROWAL","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":"BEST1, Bestrophinopathy, Mutational Tolerance, In Silico Analysis, Protein Stability, Computational Biology.","lastPublishedDoi":"10.21203/rs.3.rs-9389974/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9389974/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAbstract\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Bestrophinopathies, including Best Vitelliform Macular Dystrophy (BVMD), are caused by mutations in the \u003cem\u003eBEST1\u003c/em\u003e gene. Despite its clinical importance, the mutational tolerance of many critical residues remain poorly understood, particularly in South Asian populations where clinical data is often underrepresented.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e This study utilizes an integrated \u003cem\u003ein silico\u003c/em\u003e framework to evaluate the impact of amino acid substitutions on the Bestrophin-1 protein (PDB: 6N28). We employed a six-component computational pipeline—including PolyPhen-2 for functional impact, and DynaMut2 and mCSM for protein stability—to analyze high-risk variants. Structural models were validated using SAVES v6.1 (ERRAT and Ramachandran plots).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Our analysis achieved 100% concordance with known human clinical variants (e.g., W93C, P297S) obtained from ClinVar and HGMD. We identified specific mutational hotspots at critical residues where amino acid substitutions significantly disrupt the protein's three-dimensional discordance and stability. 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