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Many of them are extremely low homology to known proteins and cannot be annotated with homology-based or information integrative methods. To overcome this problem, we proposed a Homology Independent protein Function annotation method (HiFun) based on a unified deep-learning model by reassembling the sequence as protein language. The robustness of HiFun was evaluated using the benchmark datasets and metrics in the CAFA3 challenge. To navigate the utility of HiFun, we annotated 2 212 663 unknown proteins and discovered novel motifs in the UHGP-50 catalog. We proved that HiFun can extract latent function related structure features which empowers it ability to achieve function annotation for non-homology proteins. HiFun can substantially improve newly proteins annotation and expand our understanding of microorganisms\u2019 adaptation in various ecological niches. Moreover, we provided a free and accessible webservice at http:\/\/www.unimd.org\/HiFun, requiring only protein sequences as input, offering researchers an efficient and practical platform for predicting protein functions.<\/jats:p>","DOI":"10.1093\/bib\/bbad311","type":"journal-article","created":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T06:24:35Z","timestamp":1693463075000},"source":"Crossref","is-referenced-by-count":15,"title":["HiFun: homology independent protein function prediction by a novel protein-language self-attention model"],"prefix":"10.1093","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3381-2561","authenticated-orcid":false,"given":"Jun","family":"Wu","sequence":"first","affiliation":[{"name":"Center for Bioinformatics and Computational Biology , the Institute of Biomedical Sciences and The School of Life Sciences, , Shanghai , 200241 , China"},{"name":"East China Normal University , the Institute of Biomedical Sciences and The School of 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Zhou","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Computational Biology , the Institute of Biomedical Sciences and The School of Life Sciences, , Shanghai , 200241 , China"},{"name":"East China Normal University , the Institute of Biomedical Sciences and The School of Life Sciences, , Shanghai , 200241 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Gao","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Computational Biology , the Institute of Biomedical Sciences and The School of Life Sciences, , Shanghai , 200241 , China"},{"name":"East China Normal University , the Institute of Biomedical Sciences and The School of Life Sciences, , Shanghai , 200241 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher 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