Universal predictive scaling laws for phase separation of prion-like low complexity domains

Universal predictive scaling laws for phase separation of prion-like low complexity domains | 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 Universal predictive scaling laws for phase separation of prion-like low complexity domains Jerelle Joseph, M. Julia Maristany, Anne Aguirre Gonzalez, Rosana Collepardo-Guevara This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3068886/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 Proteins containing prion-like low complexity domains (PLDs) are common drivers of the formation of biomolecular condensates and are prone to misregulation due to amino acid mutations. Here, we exploit the accuracy of our residue-resolution coarse-grained model, Mpipi, to quantify the impact of amino acid mutations on the stability of an unprecedented set of 140 PLD mutants from six proteins (hnRNPA1, TDP43, FUS, EWSR1, RBM14, and TIA1). Our simulations reveal the existence of predictive rules that quantify the range of change in the critical solution temperature of PLDs as a function of the number and type of amino acid sequence mutations. Remarkably, these rules are consistent with the physicochemical properties of the mutations and extend across the entire family tested, suggesting universal scaling laws govern PLD phase behaviour. Our work offers a quantitative lens into how the emergent behaviour of PLD solutions varies in response to physicochemical changes of single PLD molecules. Biological sciences/Biophysics/Computational biophysics Biological sciences/Biophysics/Molecular biophysics/Thermodynamics Biological sciences/Biophysics/Intrinsically disordered proteins phase separation biomolecular condensates prion domains TDP43 FUS hnRNPA1 scaling laws TIA1 EWSR1 RBM14 low complexity domains Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SIUniversalScalingLawsNatComms.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. 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-3068886","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":212626805,"identity":"c1253eba-9101-446c-9086-edc739ba54d3","order_by":0,"name":"Jerelle Joseph","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABKElEQVRIie2RMUvEMBSAXwmkS2vXHBXvLzwpKIKcfyVQqEvBc+vgUBDa5dwriP4Fp5srgboUbr2hw5VCJodOcpu2154Otjc75BvySF4+3nsJgELxD9HCZtnMgbQbAgEA/U3ycYXjXsl7JT2gdCnsItGi/uSQQuKHcsPxUrcskVW3z8XNkX1fVnVQgKX7ONjY4t1Bjh6ZJN6187iUF9Fx5mCaS5gsPoaVxKOMoyC4Ns5scymQMp+yt0gArkeqvEh9y/GL4Gr1aZtPO0XftsrVmJJQ2oyfEkx9apthVwV2VdjYLB5pGnPbWc4dI5ON4jksz4XBcjkfUk7jTKvrYOY2LyYr467AaeKWdRCIEyt2XweVsIsudJ+Y/mSMoest0z7O/igKhUKh2PMNyA9f657sMS0AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-4525-180X","institution":"Princeton University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jerelle","middleName":"","lastName":"Joseph","suffix":""},{"id":212626806,"identity":"27bf1fdb-37d3-4eb6-899f-8ad0ffa82445","order_by":1,"name":"M. 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Here, we exploit the accuracy of our residue-resolution coarse-grained model, Mpipi, to quantify the impact of amino acid mutations on the stability of an unprecedented set of 140 PLD mutants from six proteins (hnRNPA1, TDP43, FUS, EWSR1, RBM14, and TIA1). Our simulations reveal the existence of predictive rules that quantify the range of change in the critical solution temperature of PLDs as a function of the number and\r\ntype of amino acid sequence mutations. Remarkably, these rules are consistent with the physicochemical properties of the mutations and extend across the entire family tested, suggesting universal scaling laws govern PLD phase behaviour. 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