Sampling Conformational Ensembles of Highly Dynamic Proteins via Generative Deep Learning

Sampling Conformational Ensembles of Highly Dynamic Proteins via Generative Deep Learning | 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 Sampling Conformational Ensembles of Highly Dynamic Proteins via Generative Deep Learning Chia-en Chang, Talant Ruzmetov, Ta I Hung, Saisri Padmaja Jonnalagedda, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4301803/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 Proteins are inherently dynamic, and their conformational ensembles are functionally important in biology. Large-scale motions may govern protein structure–function relationship, and numerous transient but stable conformations of intrinsically disordered proteins (IDPs) can play a crucial role in biological function. Investigating conformational ensembles to understand regulations and disease-related aggregations of IDPs is challenging both experimentally and computationally. In this paper first an unsupervised deep learning-based model, termed Internal Coordinate Net (ICoN), is developed that learns the physical principles of conformational changes from molecular dynamics (MD) simulation data. Second, interpolating data points in the learned latent space are selected that rapidly identify novel synthetic conformations with sophisticated and large-scale sidechains and backbone arrangements. Third, with the highly dynamic amyloid-β1-42 (Aβ42) monomer, our deep learning model provided a comprehensive sampling of Aβ42’s conformational landscape. Analysis of these synthetic conformations revealed conformational clusters that can be used to rationalize experimental findings. Additionally, the method can identify novel conformations with important interactions in atomistic details that are not included in the training data. New synthetic conformations showed distinct sidechain rearrangements that are probed by our EPR and amino acid substitution studies. The proposed approach is highly transferable and can be used for any available data for training. The work also demonstrated the ability for deep learning to utilize learned natural atomistic motions in protein conformation sampling. Biological sciences/Structural biology/Molecular modelling Biological sciences/Biophysics/Computational biophysics Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryMaterials.pdf 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-4301803","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":298510447,"identity":"93558561-587d-40f4-8108-f074bdacf97a","order_by":0,"name":"Chia-en 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