Single-Residue Solvation Perturbations Regulate Global Protein Architecture and Function

Single-Residue Solvation Perturbations Regulate Global Protein Architecture and Function | 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 Single-Residue Solvation Perturbations Regulate Global Protein Architecture and Function Di Li, Yingya Liu, Jihang Zhai, Shanshan Cao, Huiying Guo, Hengwei Zhang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7201385/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Mar, 2026 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Protein-water interactions fundamentally shape the structure, stability, dynamics, and functionality of proteins. However, the heterogeneous nature of the protein-water interface and the disparity in their dynamic interplay make it challenging to understand how local water perturbations influence protein structural dynamics over space and time. In this study, we introduce a photochromic molecule, spiropyran, to modify a specific residue of proteins, thereby achieving a reversible, residue-specific, and amplified perturbation on the hydrophobicity of protein surfaces. With the aid of controlled, amplified hydrophobic perturbations, we reveal that even subtle, residue-level changes in hydrophobicity induce significant global alterations in protein hydration patterns. These hydration shifts propagate in an amino acid sequence-dependent manner, initiating a “butterfly effect” that dramatically influences overall protein architecture and catalytic performance. Our findings establish that interfacial water networks not only capture the surface physicochemical patterns of proteins but also mediate the propagation of local perturbations into broader structural and functional fluctuations. By shifting the paradigm from “structure-function” to “structure-hydration-function”, our work provides innovative perspectives into understanding protein architecture and guiding future drug design strategies. Physical sciences/Chemistry/Biochemistry/Biophysical chemistry Biological sciences/Biochemistry/Protein folding Full Text Additional Declarations There is NO Competing Interest. Supplementary Files supportinginformation.pdf supplementary information Cite Share Download PDF Status: Published Journal Publication published 10 Mar, 2026 Read the published version in Nature Communications → 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-7201385","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":497375374,"identity":"1ec7002f-8c0b-4c12-91a0-f15d45f5a328","order_by":0,"name":"Di 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