ConTP: Reshaping transporter functional space to resolve substrate specificity beyond evolutionary proximity

ConTP: Reshaping transporter functional space to resolve substrate specificity beyond evolutionary proximity | 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 ConTP: Reshaping transporter functional space to resolve substrate specificity beyond evolutionary proximity Xin Gao, Chenjie Feng, Wenjia He, Junbo Yin, Xiaopeng Xu, Min Zhou, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9137605/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 Membrane transporter annotation has long relied on a homology-centric paradigm that treats evolutionary proximity as a proxy for substrate specificity. Yet transporter functional space is intrinsically long-tailed, partially multi-label, and often decoupled from phylogeny, creating systematic blind spots in substrate-level inference. We reformulate substrate annotation as a chemically coherent multi-label problem and construct benchmarks spanning 70 fine-grained substrate types and 1,352 TC families. We introduce ConTP, an evolution-informed contrastive framework that realigns pretrained protein language model embeddings around substrate semantics rather than sequence similarity, enabling taxon-agnostic, prototype-based inference. In this aligned manifold, cross-family convergence, exemplified by sodium transport across distinct TC superfamilies, and authentic multi-substrate specificity in NRAMP transporters are faithfully recovered. Furthermore, projection of generated sequences exposes substrate-fidelity violations in contemporary design models. Together, these findings support a geometry-aware view of transporter specificity beyond raw evolutionary similarity. Biological sciences/Computational biology and bioinformatics/Machine learning Biological sciences/Computational biology and bioinformatics/Protein analysis/Protein sequence analyses Biological sciences/Computational biology and bioinformatics/Protein function predictions Biological sciences/Computational biology and bioinformatics/Sequence annotation Biological sciences/Plant sciences/Plant molecular biology Full Text Additional Declarations There is NO Competing Interest. Supplementary Files ConTPSIsubmit.docx Supplemental Information for ConTP: Reshaping transporter functional space to resolve substrate specificity beyond evolutionary proximity 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-9137605","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":608985376,"identity":"6ad67e17-fe50-4160-9d08-2caef85f5687","order_by":0,"name":"Xin 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