{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T15:07:15Z","timestamp":1780067235303,"version":"3.54.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T00:00:00Z","timestamp":1719532800000},"content-version":"vor","delay-in-days":36,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,5,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Accurate understanding of the biological functions of enzymes is vital for various tasks in both pathologies and industrial biotechnology. However, the existing methods are usually not fast enough and lack explanations on the prediction results, which severely limits their real-world applications. Following our previous work, DEEPre, we propose a new interpretable and fast version (ifDEEPre) by designing novel self-guided attention and incorporating biological knowledge learned via large protein language models to accurately predict the commission numbers of enzymes and confirm their functions. Novel self-guided attention is designed to optimize the unique contributions of representations, automatically detecting key protein motifs to provide meaningful interpretations. Representations learned from raw protein sequences are strictly screened to improve the running speed of the framework, 50 times faster than DEEPre while requiring 12.89 times smaller storage space. Large language modules are incorporated to learn physical properties from hundreds of millions of proteins, extending biological knowledge of the whole network. Extensive experiments indicate that ifDEEPre outperforms all the current methods, achieving more than 14.22% larger F1-score on the NEW dataset. Furthermore, the trained ifDEEPre models accurately capture multi-level protein biological patterns and infer evolutionary trends of enzymes by taking only raw sequences without label information. Meanwhile, ifDEEPre predicts the evolutionary relationships between different yeast sub-species, which are highly consistent with the ground truth. Case studies indicate that ifDEEPre can detect key amino acid motifs, which have important implications for designing novel enzymes. A web server running ifDEEPre is available at https:\/\/proj.cse.cuhk.edu.hk\/aihlab\/ifdeepre\/ to provide convenient services to the public. Meanwhile, ifDEEPre is freely available on GitHub at https:\/\/github.com\/ml4bio\/ifDEEPre\/.<\/jats:p>","DOI":"10.1093\/bib\/bbae225","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T23:39:28Z","timestamp":1719617968000},"source":"Crossref","is-referenced-by-count":8,"title":["ifDEEPre: large protein language-based deep learning enables interpretable and fast predictions of enzyme commission numbers"],"prefix":"10.1093","volume":"25","author":[{"given":"Qingxiong","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Computer Science and Engineering, The Chinese University of Hong Kong , Hong Kong SAR , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Hong Kong Baptist University , Hong Kong SAR , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering, The Chinese University of Hong Kong , Hong Kong SAR , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering, The Chinese University of Hong Kong , Hong Kong SAR , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeliang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of Rochester , Rochester, New York State , USA"},{"name":"School of Computer Science and Technology, Huazhong University of Science and Technology , Wuhan , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiancheng","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Software, Shandong University , Jinan , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Engineering, The Chinese University of Hong Kong , Hong Kong SAR , China"},{"name":"The CUHK Shenzhen Research Institute , Nanshan, Shenzhen , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,6,28]]},"reference":[{"issue":"3","key":"2024062823391356700_ref1","doi-asserted-by":"crossref","first-page":"bbad065","DOI":"10.1093\/bib\/bbad065","article-title":"A review of enzyme design in catalytic stability by artificial intelligence","volume":"24","author":"Ming","year":"2023","journal-title":"Brief Bioinform"},{"issue":"6639","key":"2024062823391356700_ref2","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1126\/science.adf2465","article-title":"Enzyme function prediction using contrastive 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Science","volume":"7","author":"Huang","year":"2021","journal-title":"Advances"},{"key":"2024062823391356700_ref44","doi-asserted-by":"crossref","first-page":"104793","DOI":"10.1016\/j.antiviral.2020.104793","article-title":"Remdesivir and sars-cov-2: structural requirements at both nsp12 rdrp and nsp14 exonuclease active-sites","volume":"178","author":"Shannon","year":"2020","journal-title":"Antiviral Res"},{"key":"2024062823391356700_ref45","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1093\/nar\/gkr367","article-title":"Hmmer web server: interactive sequence similarity searching","volume":"39","author":"Finn","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"2024062823391356700_ref46","doi-asserted-by":"crossref","DOI":"10.1038\/s41563-023-01683-1","article-title":"Accurate computational design of three-dimensional protein crystals","volume":"22","author":"Li","year":"2023","journal-title":"Nat Mater"},{"issue":"1","key":"2024062823391356700_ref47","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1038\/s41467-023-38414-8","article-title":"Small-sample learning reveals propionylation in determining global protein homeostasis","volume":"14","author":"Shui","year":"2023","journal-title":"Nat Commun"},{"key":"2024062823391356700_ref48","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1038\/s41557-023-01252-8","article-title":"Site-specific bioorthogonal protein labelling by tetrazine ligation using endogenous $\\beta $-amino acid dienophiles","volume":"15","author":"Richter","year":"2023","journal-title":"Nat Chem"}],"container-title":["Briefings in Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/25\/4\/bbae225\/58358162\/bbae225.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/25\/4\/bbae225\/58358162\/bbae225.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T23:40:09Z","timestamp":1719618009000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bib\/article\/doi\/10.1093\/bib\/bbae225\/7701117"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,23]]},"references-count":48,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,5,23]]}},"URL":"https:\/\/doi.org\/10.1093\/bib\/bbae225","relation":{},"ISSN":["1467-5463","1477-4054"],"issn-type":[{"value":"1467-5463","type":"print"},{"value":"1477-4054","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,7]]},"published":{"date-parts":[[2024,5,23]]},"article-number":"bbae225"}}