Structure Alignment-driven Cross-Graph Modeling for Functional RNA Design

Structure Alignment-driven Cross-Graph Modeling for Functional RNA Design | 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 Structure Alignment-driven Cross-Graph Modeling for Functional RNA Design Xiaoyong Pan, Shengfan Wang, Jun Wang, Xiaojian Liu, Weimin Zhu, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7169944/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 RNAs are critical for biological processes, with their biological functions closely tied to their three-dimensional structures. RNA inverse folding, the design of RNA sequences that fold into target 3D structures, is a complex challenge due to the dynamic and unstable nature of RNA structures. Motivated by evolutionary conservation concepts from structure prediction, we present a novel RNA design approach AlignIF, which leverages multiple structure alignment (MStA) with cross-graph modeling to capture evolutionarily conserved structural patterns at the structural level, facilitating RNA sequence design. AlignIF outperforms existing state-of-the-art methods by a large margin in key metrics, including sequence recovery, perplexity, and foldability. Notably, it enables the design of entire RNA families rather than being restricted to recapitulating native sequences. Furthermore, AlignIF effectively generates functional RNA fluorescent aptamers and self-cleaving ribozymes, as experimentally validated by their respective fluorescent signals or cleavage activity. Importantly, two of the ten designed aptamers show enhanced fluorescence compared to the wild-type aptamer due to the increased fluorophore binding capacity, and other two exhibit improved binding affinity toward the target molecule, highlighting the potential of AlignIF for engineering novel functional RNAs. Biological sciences/Computational biology and bioinformatics/Machine learning Biological sciences/Systems biology/Synthetic biology Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupportInformation.docx Support 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. 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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-7169944","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":489660081,"identity":"3b991f63-0d74-4ad4-bfb2-cb4cd7bae758","order_by":0,"name":"Xiaoyong 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