Accurate predictions of conformational ensembles of disordered proteins with STARLING

Accurate predictions of conformational ensembles of disordered proteins with STARLING | 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 Biological Sciences - Article Accurate predictions of conformational ensembles of disordered proteins with STARLING Alex Holehouse, Borna Novak, Jeffrey Lotthammer, Ryan Emenecker This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6100260/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Feb, 2026 Read the published version in Nature → Version 1 posted You are reading this latest preprint version Abstract Intrinsically disordered proteins and regions (collectively IDRs) are found across all kingdoms of life and play critical roles in virtually every eukaryotic cellular process. In contrast to folded proteins, IDRs lack a stable 3D structure and are instead described in terms of a conformational ensemble, a collection of energetically accessible interconverting structures. This unique structural plasticity facilitates diverse molecular recognition and function; thus, a convenient way to view IDRs is through their ensembles. Here, we combine advances in physics-based force fields for IDPs with the power of modern multi-scale generative modeling to develop STARLING, an approach for the rapid and accurate prediction of IDR ensembles directly from sequence. STARLING enables ensembles of hundreds of conformers to be generated in seconds and works on GPUs and CPUs. This, in turn, dramatically lowers the barrier to the computational interrogation of IDR function through the lens of emergent biophysical properties complementing bioinformatic protein sequence analysis. We evaluate STARLING’s accuracy against extant experimental data and offer a series of vignettes illustrating how STARLING can enable rapid hypothesis generation for IDR function and aid the interpretation of experimental data. Biological sciences/Biophysics/Intrinsically disordered proteins Biological sciences/Biophysics/Computational biophysics Full Text Additional Declarations Yes there is potential Competing Interest. A.S.H. is on the scientific advisory board (SAB) of Prose Foods. All other authors declare no competing interests. Supplementary Files STARLINGsupplement.pdf STARLING supplementary material Cite Share Download PDF Status: Published Journal Publication published 18 Feb, 2026 Read the published version in Nature → 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. 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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-6100260","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":425271418,"identity":"103f4400-6ed8-4a91-b855-99c32abbe4b9","order_by":0,"name":"Alex Holehouse","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAUlEQVRIie3PMWrDMBSAYQlDurzWq4zb9AoKhiw27VViBMoS7xkCNRh8hhR6CI0dFQTqYqpVJUu6dE63dAmVk6yizZZBP8ighz8kIRQKXWJXbuEa3SJy2Bb9B0uEIj+JjgROhB9GZxH1N4mbSBP8WkCcNjrZzU0pjJESzfOy9hCiBozijkPyonkK3boUlrlTuqmXIAWjDW4VUDsbp7hdV8K6i7mJl9yreNv/AI+OJD/790oY5cjeT6gCfDyFzMbkupaVkO5iuPaTkRpktGw5EMtZDpo9PVtG5URPMx8ZvjVf5LsthvGSrT52i4fsxqw+N9tFfud9ft/kH5NQKBQKndMvK+lcVQH1ZJsAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-4155-5729","institution":"Washington University in St. Louis","correspondingAuthor":true,"prefix":"","firstName":"Alex","middleName":"","lastName":"Holehouse","suffix":""},{"id":425271419,"identity":"2a767125-b682-47b4-b067-1ea0d44ad7a4","order_by":1,"name":"Borna Novak","email":"","orcid":"","institution":"Washington University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Borna","middleName":"","lastName":"Novak","suffix":""},{"id":425271420,"identity":"60f50e2d-4c3a-41d7-bfa9-01a7e7b0ccec","order_by":2,"name":"Jeffrey Lotthammer","email":"","orcid":"","institution":"Washington University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jeffrey","middleName":"","lastName":"Lotthammer","suffix":""},{"id":425271421,"identity":"2bde84c3-2b08-411b-b917-3f44be8eb40a","order_by":3,"name":"Ryan Emenecker","email":"","orcid":"https://orcid.org/0000-0001-7055-2773","institution":"Washington University in St. Louis","correspondingAuthor":false,"prefix":"","firstName":"Ryan","middleName":"","lastName":"Emenecker","suffix":""}],"badges":[],"createdAt":"2025-02-25 00:25:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6100260/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6100260/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41586-026-10141-2","type":"published","date":"2026-02-18T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":102977083,"identity":"77c6ef5d-6433-4d96-82e2-a595fbdd2c8a","added_by":"auto","created_at":"2026-02-19 08:05:54","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2055656,"visible":true,"origin":"","legend":"Article File","description":"","filename":"STARLINGmain.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6100260/v1_covered_b0f83b4f-2fce-49c9-b483-17eaf0fee0c0.pdf"},{"id":78102686,"identity":"1b1f4d67-8d7c-43cc-a7d7-e55f1141b149","added_by":"auto","created_at":"2025-03-10 02:32:55","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":7533731,"visible":true,"origin":"","legend":"STARLING supplementary material","description":"","filename":"STARLINGsupplement.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6100260/v1/d910b7871af13f16fda0341f.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nA.S.H. is on the scientific advisory board (SAB) of Prose Foods. 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