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Here, we introduce SCREEN, a graph neural network for the high-throughput prediction of catalytic residues via the integration of enzyme functional and structural information. SCREEN constructs residue representations based on spatial arrangements and incorporates enzyme function priors into such representations through contrastive learning. We demonstrate that SCREEN (1) consistently outperforms currently-available predictors; (2) provides accurate results when applied to inferred enzyme structures; and (3) generalizes well to enzymes dissimilar from those in the training set. We also show that the putative catalytic residues predicted by SCREEN mimic key structural and biophysical characteristics of native catalytic residues. Moreover, using experimental datasets, we show that SCREEN\u2019s predictions can be used to distinguish residues with a high mutation tolerance from those likely to cause functional loss when mutated, indicating that this tool might be used to infer disease-associated mutations. SCREEN is publicly available at https:\/\/github.com\/BioColLab\/SCREEN and https:\/\/ngdc.cncb.ac.cn\/biocode\/tool\/7580.<\/jats:p>","DOI":"10.1093\/gpbjnl\/qzae094","type":"journal-article","created":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T16:42:26Z","timestamp":1735231346000},"source":"Crossref","is-referenced-by-count":7,"title":["SCREEN: A Graph-based Contrastive Learning Tool to Infer Catalytic Residues and Assess Enzyme Mutations"],"prefix":"10.1093","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6676-5727","authenticated-orcid":false,"given":"Tong","family":"Pan","sequence":"first","affiliation":[{"name":"Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University , Clayton, VIC 3800,","place":["Australia"]},{"name":"Monash Biomedicine Discovery Institute-Wenzhou Medical University Alliance in Clinical and Experimental Biomedicine, Monash University , Clayton, VIC 3800,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6220-7475","authenticated-orcid":false,"given":"Yue","family":"Bi","sequence":"additional","affiliation":[{"name":"Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University , Clayton, VIC 3800,","place":["Australia"]},{"name":"Monash Biomedicine Discovery Institute-Wenzhou Medical University Alliance in Clinical and Experimental Biomedicine, Monash University , Clayton, VIC 3800,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4444-6197","authenticated-orcid":false,"given":"Xiaoyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University , Clayton, VIC 3800,","place":["Australia"]},{"name":"Monash Biomedicine Discovery Institute-Wenzhou Medical University Alliance in Clinical and Experimental Biomedicine, Monash University , Clayton, VIC 3800,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1792-0121","authenticated-orcid":false,"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University , Clayton, VIC 3800,","place":["Australia"]},{"name":"School of Computer Science and Engineering, Nanjing University of Science and Technology , Nanjing 210094,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9963-5169","authenticated-orcid":false,"given":"Geoffrey I","family":"Webb","sequence":"additional","affiliation":[{"name":"Department of Data Science and Artificial Intelligence, Monash University , Clayton, VIC 3800,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4423-1690","authenticated-orcid":false,"given":"Robin B","family":"Gasser","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, Melbourne Veterinary School, The University of Melbourne , Parkville, VIC 3010,","place":["Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7749-0314","authenticated-orcid":false,"given":"Lukasz","family":"Kurgan","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Virginia Commonwealth University , Richmond, VA 23284,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8031-9086","authenticated-orcid":false,"given":"Jiangning","family":"Song","sequence":"additional","affiliation":[{"name":"Monash Biomedicine Discovery Institute and Department of Biochemistry and 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