Spatial Covariant Management of Thermodynamics Contributes to Protein Fold Function through Quality Assurance

Spatial Covariant Management of Thermodynamics Contributes to Protein Fold Function through Quality Assurance | 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 Spatial Covariant Management of Thermodynamics Contributes to Protein Fold Function through Quality Assurance Frederic Angles, Chao Wang, William Balch This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-717846/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Although the impact of genome variation on the thermodynamic properties of the protein fold has been studied in vitro, it remains a challenge to assign these relationships across the entire polypeptide sequence in vivo. Using the Gaussian process regression-based principle of Spatial CoVariance (SCV), we globally assign on a residue-by-residue the biological thermodynamic properties contributing to the functional fold in the cell using CFTR as an example. We demonstrate the existence of a thermodynamically sensitive region of the CFTR fold involving the interface between NBD1 and ICL4 that contributes to the endoplasmic reticulum (ER) export. At the cell surface a new set of residues contribute uniquely to the management of channel function. These results support a general 'quality assurance' (QA) view of global protein fold management as an SCV principle describing the differential pre- and post-ER residue interactions contributing to compartmentalization of the energetics of the protein fold for function. General Cell Biology & Physiology Molecular Biology protein fold genome variations Spatial CoVarience Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SuppTable1.xlsx Table S1 SuppTable2.xlsx Table S2 Supplementary.pdf Supplementary Figures S1 - S9 Cite Share Download PDF Status: Under Review 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-717846","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":41203210,"identity":"c62a4652-5946-4051-824e-ce583e61c219","order_by":0,"name":"Frederic Angles","email":"","orcid":"","institution":"The Scripps Research Institute","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Frederic","middleName":"","lastName":"Angles","suffix":""},{"id":41203211,"identity":"1dba8b40-c085-42cd-a990-dcf8f8d0d202","order_by":1,"name":"Chao Wang","email":"","orcid":"","institution":"The Scripps Research 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15:28:03","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1054868,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-717846/v1_covered.pdf"},{"id":11810550,"identity":"12701016-505e-451d-9f85-e739feccd8ba","added_by":"auto","created_at":"2021-07-26 15:27:56","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10677,"visible":true,"origin":"","legend":"Table S1","description":"","filename":"SuppTable1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-717846/v1/a39ed28cb54517cf028ab157.xlsx"},{"id":11810429,"identity":"93c092b3-2fa8-42b5-b7c3-831fbaeeb61f","added_by":"auto","created_at":"2021-07-26 15:24:56","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":105582,"visible":true,"origin":"","legend":"Table 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Using the Gaussian process regression-based principle of Spatial CoVariance (SCV), we globally assign on a residue-by-residue the biological thermodynamic properties contributing to the functional fold in the cell using CFTR as an example. We demonstrate the existence of a thermodynamically sensitive region of the CFTR fold involving the interface between NBD1 and ICL4 that contributes to the endoplasmic reticulum (ER) export. At the cell surface a new set of residues contribute uniquely to the management of channel function. 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