Allostery can convert binding free energies into concerted domain motions in enzymes

Allostery can convert binding free energies into concerted domain motions in enzymes | 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 Allostery can convert binding free energies into concerted domain motions in enzymes Giovanni Maglia, Nicole Galenkamp, Sarah Zernia, Yulan Van Oppen, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4304189/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Nov, 2024 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Enzymes’ mechanisms are typically inferred from structural data. However, understanding proteins’ functions requires unravelling the intricate dynamic interplay between dynamics, conformational substates and multiple protein structures. Here, we investigate the catalytic cycle of adenylate kinase (AK), an enzyme that catalyzes the interconversion of the various adenosine phosphates (ATP, ADP, and AMP). Our findings reveal that allosteric interactions enable converting ligands and cofactor binding energies into directional conformational changes of the two catalytic domains of AK. These coordinated motions emerged to control the exact sequence of ligand binding, the affinity for the three different substrates, and guiding the reactants along the reaction coordinates. Interestingly, we found that about 10% of enzymes showed altered allosteric regulation and ligand affinities, indicating that a subset of enzymes folded in alternative catalytically active forms. Since molecules or proteins might be able to selectively stabilize one of these multiple folds, this observation suggests an evolutionary path for allostery in enzymes. In AK, this complex catalytic framework has likely emerged to prevent futile ATP/ADP hydrolysis and to finely tune the enzyme for different energy needs of the cell. Biological sciences/Biophysics/Single-molecule biophysics Biological sciences/Biochemistry/Kinases Biological sciences/Biochemistry/Enzyme mechanisms Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryInformation.pdf RawData.zip Supplementary Data Cite Share Download PDF Status: Published Journal Publication published 22 Nov, 2024 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. 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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-4304189","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":297291849,"identity":"6826294e-3f1e-4b0d-b0f3-cd31c22c5183","order_by":0,"name":"Giovanni 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However, understanding proteins’ functions requires unravelling the intricate dynamic interplay between dynamics, conformational substates and multiple protein structures. Here, we investigate the catalytic cycle of adenylate kinase (AK), an enzyme that catalyzes the interconversion of the various adenosine phosphates (ATP, ADP, and AMP). Our findings reveal that allosteric interactions enable converting ligands and cofactor binding energies into directional conformational changes of the two catalytic domains of AK. These coordinated motions emerged to control the exact sequence of ligand binding, the affinity for the three different substrates, and guiding the reactants along the reaction coordinates. Interestingly, we found that about 10% of enzymes showed altered allosteric regulation and ligand affinities, indicating that a subset of enzymes folded in alternative catalytically active forms. 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