Solvent-responsive solid/liquid phase transitions of condensates depend on trade-off molecular interactions

Solvent-responsive solid/liquid phase transitions of condensates depend on trade-off molecular interactions | 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 Solvent-responsive solid/liquid phase transitions of condensates depend on trade-off molecular interactions Ho Cheung Shum, Feipeng Chen, Yongxu Han, Huiyanchen Li, Xiufeng Li, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7393420/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 Nature effectively leverages multivalent interactions among fundamental building blocks in solvents to build structures of remarkable complexity and functionality. For example, biomolecular condensates, formed through phase separation of biomolecules driven by multivalent interactions, play crucial roles in forming adhesives for marine animals and orchestrating enzymatic reactions within cells. However, understanding how molecular interactions dictate macroscopic properties of condensates remains a substantial challenge. Here, combining multiscale experiments and molecular dynamics simulations, we demonstrate that different molecular interactions exhibit divergent solvent-responsiveness, the balance of which dictates the material properties and phase transitions of condensates. In particular, condensates with mainly charged sidechains exhibit hydrophilic environments and are solidified upon alcohol addition due to strengthened electrostatic interactions. In contrast, condensates rich in aromatic residues show relatively hydrophobic environments and are dissolved in the presence of alcohol due to weakened cation-π and π-π interactions. These findings are generalized into a predictive framework correlating condensate phase transitions to the hydrophobic scale of constituent monomers, applicable to both synthetic polyelectrolytes and intrinsically disordered proteins. As a proof of concept, we leverage these insights to engineer adhesives that are recyclable or maintain stability under varying cosolvent conditions. Our findings not only resolve a conundrum in the field but also bridge molecular-level interactions with macroscopic properties and phase transitions of condensates, offering promising insights for industrial and biomedical applications. Physical sciences/Materials science/Soft materials/Polymers Physical sciences/Engineering/Chemical engineering Biological sciences/Biophysics/Intrinsically disordered proteins Full Text Additional Declarations There is NO Competing Interest. Supplementary Files V30SIbidirectionalphaseseparationFP2025.pdf Supplementary Information 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-7393420","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":506810226,"identity":"acc0d497-bf4b-4b0e-b686-bfada85fae6e","order_by":0,"name":"Ho Cheung Shum","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYFACHiCuAJNAwMbAYMBDlJYzDDw8pGlhbGNgIF4Lf//ZY1I359nJ2EvkGDB8KDvMYM5zAL8WiRt5adK525J5eIBaGGecO8xg2dtAwJobPGZALQfAWph52w4zGJwnoEP+/BmgljlQLX+J0WJwIAeopQGqhRGk5SwBhxneyDG2zjkG9MuZZwUHe86l8xicOYBfi9z5M4a3c2rs7Nnbkzc++FFmLWdwJoGAy+BAIIEBZDzhiEQAfgLuGQWjYBSMgpELACNUPawk875bAAAAAElFTkSuQmCC","orcid":"","institution":"Department of Chemistry and Department of Biomedical Engineering, City University of Hong Kong","correspondingAuthor":true,"prefix":"","firstName":"Ho","middleName":"Cheung","lastName":"Shum","suffix":""},{"id":506810227,"identity":"0e3e2de4-f063-4390-8a62-da18d708ff8e","order_by":1,"name":"Feipeng Chen","email":"","orcid":"","institution":"University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Feipeng","middleName":"","lastName":"Chen","suffix":""},{"id":506810228,"identity":"d2521ec4-7b66-4fa5-8006-afa0a615d072","order_by":2,"name":"Yongxu Han","email":"","orcid":"","institution":"The Chinese University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Yongxu","middleName":"","lastName":"Han","suffix":""},{"id":506810229,"identity":"5688a79b-ccb7-4f8f-83c4-deeec05bfc51","order_by":3,"name":"Huiyanchen Li","email":"","orcid":"","institution":"Advanced Biomedical Instrumentation Centre","correspondingAuthor":false,"prefix":"","firstName":"Huiyanchen","middleName":"","lastName":"Li","suffix":""},{"id":506810230,"identity":"6f8c8691-8d7c-4311-ae9a-744658bc1115","order_by":4,"name":"Xiufeng Li","email":"","orcid":"https://orcid.org/0000-0002-7615-4693","institution":"Advanced Biomedical Instrumentation Centre","correspondingAuthor":false,"prefix":"","firstName":"Xiufeng","middleName":"","lastName":"Li","suffix":""},{"id":506810231,"identity":"f7e83ef6-dd49-4b6d-82ad-67d0aaf534ef","order_by":5,"name":"Wei Guo","email":"","orcid":"","institution":"University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Guo","suffix":""},{"id":506810232,"identity":"817b743f-f725-4373-aff8-bb005d073be7","order_by":6,"name":"Changjin Wu","email":"","orcid":"https://orcid.org/0000-0001-9885-9128","institution":"University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Changjin","middleName":"","lastName":"Wu","suffix":""},{"id":506810233,"identity":"485bbba8-4bda-4d19-989a-621e5255cf1f","order_by":7,"name":"Jiang Xia","email":"","orcid":"https://orcid.org/0000-0001-8112-7625","institution":"The Chinese University of Hong Kong","correspondingAuthor":false,"prefix":"","firstName":"Jiang","middleName":"","lastName":"Xia","suffix":""},{"id":506810234,"identity":"5c58d54e-c09e-4276-9ab1-8bfa8f823985","order_by":8,"name":"Xiangze Zeng","email":"","orcid":"https://orcid.org/0000-0002-9848-3033","institution":"Hong Kong Baptist University","correspondingAuthor":false,"prefix":"","firstName":"Xiangze","middleName":"","lastName":"Zeng","suffix":""}],"badges":[],"createdAt":"2025-08-17 15:55:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7393420/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7393420/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107868774,"identity":"c96449b1-599d-455f-a1f1-b636bd2ce287","added_by":"auto","created_at":"2026-04-27 07:33:41","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1365648,"visible":true,"origin":"","legend":"Article File","description":"","filename":"V43BidirectionalphasetransitionFP2025XIA.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7393420/v1_covered_a7f95e7b-6137-41d9-9f42-4585ac350a0e.pdf"},{"id":90139193,"identity":"dae89c1a-3cee-4b4b-aad9-5cd89c8d2357","added_by":"auto","created_at":"2025-08-29 03:15:41","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1927290,"visible":true,"origin":"","legend":"Supplementary Information","description":"","filename":"V30SIbidirectionalphaseseparationFP2025.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7393420/v1/6af410278c7ec6938c251221.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Solvent-responsive solid/liquid phase transitions of condensates depend on trade-off molecular interactions","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"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":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7393420/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7393420/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Nature effectively leverages multivalent interactions among fundamental building blocks in solvents to build structures of remarkable complexity and functionality. For example, biomolecular condensates, formed through phase separation of biomolecules driven by multivalent interactions, play crucial roles in forming adhesives for marine animals and orchestrating enzymatic reactions within cells. However, understanding how molecular interactions dictate macroscopic properties of condensates remains a substantial challenge. Here, combining multiscale experiments and molecular dynamics simulations, we demonstrate that different molecular interactions exhibit divergent solvent-responsiveness, the balance of which dictates the material properties and phase transitions of condensates. In particular, condensates with mainly charged sidechains exhibit hydrophilic environments and are solidified upon alcohol addition due to strengthened electrostatic interactions. In contrast, condensates rich in aromatic residues show relatively hydrophobic environments and are dissolved in the presence of alcohol due to weakened cation-π and π-π interactions. These findings are generalized into a predictive framework correlating condensate phase transitions to the hydrophobic scale of constituent monomers, applicable to both synthetic polyelectrolytes and intrinsically disordered proteins. As a proof of concept, we leverage these insights to engineer adhesives that are recyclable or maintain stability under varying cosolvent conditions. Our findings not only resolve a conundrum in the field but also bridge molecular-level interactions with macroscopic properties and phase transitions of condensates, offering promising insights for industrial and biomedical applications.","manuscriptTitle":"Solvent-responsive solid/liquid phase transitions of condensates depend on trade-off molecular interactions","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-29 03:15:36","doi":"10.21203/rs.3.rs-7393420/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5014dee1-a430-4041-86e9-99606a1b7939","owner":[],"postedDate":"August 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":53830584,"name":"Physical sciences/Materials science/Soft materials/Polymers"},{"id":53830585,"name":"Physical sciences/Engineering/Chemical engineering"},{"id":53830586,"name":"Biological sciences/Biophysics/Intrinsically disordered proteins"}],"tags":[],"updatedAt":"2026-05-13T04:05:17+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-29 03:15:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7393420","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7393420","identity":"rs-7393420","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}