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Stable protein complexes\u2014or macromolecular machines\u2014are, in turn, the key functional entities mediating and modulating most biological processes. Although identifying protein complexes and their subunit composition can now be done inexpensively and at scale, determining their function remains challenging and labor intensive. This study describes Protein Complex Function predictor (PCfun), the first computational framework for the systematic annotation of protein complex functions using Gene Ontology (GO) terms. PCfun is built upon a word embedding using natural language processing techniques based on 1 million open access PubMed Central articles. Specifically, PCfun leverages two approaches for accurately identifying protein complex function, including: (i) an unsupervised approach that obtains the nearest neighbor (NN) GO term word vectors for a protein complex query vector and (ii) a supervised approach using Random Forest (RF) models trained specifically for recovering the GO terms of protein complex queries described in the CORUM protein complex database. PCfun consolidates both approaches by performing a hypergeometric statistical test to enrich the top NN GO terms within the child terms of the GO terms predicted by the RF models. The documentation and implementation of the PCfun package are available at https:\/\/github.com\/sharmavaruns\/PCfun. We anticipate that PCfun will serve as a useful tool and novel paradigm for the large-scale characterization of protein complex function.<\/jats:p>","DOI":"10.1093\/bib\/bbac239","type":"journal-article","created":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T22:05:47Z","timestamp":1655762747000},"source":"Crossref","is-referenced-by-count":1,"title":["PCfun: a hybrid computational framework for systematic characterization of protein complex function"],"prefix":"10.1093","volume":"23","author":[{"given":"Varun S","family":"Sharma","sequence":"first","affiliation":[{"name":"Department of Biology, Institute of Molecular Systems Biology , ETH Zurich, Switzerland"},{"name":"CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences , Vienna, Austria"}]},{"given":"Andrea","family":"Fossati","sequence":"additional","affiliation":[{"name":"Quantitative Biosciences Institute (QBI) and Department of Cellular and Molecular Pharmacology, University of California , San Francisco, CA 94158, USA"},{"name":"J. David Gladstone Institutes , San Francisco, CA 94158, USA"}]},{"given":"Rodolfo","family":"Ciuffa","sequence":"additional","affiliation":[{"name":"Department of Biology, Institute of Molecular Systems Biology , ETH Zurich, Switzerland"}]},{"given":"Marija","family":"Buljan","sequence":"additional","affiliation":[{"name":"Empa - Swiss Federal Laboratories for Materials Science and Technology , St. Gallen, Switzerland"},{"name":"Swiss Institute of Bioinformatics (SIB) , Lausanne, Switzerland"}]},{"given":"Evan G","family":"Williams","sequence":"additional","affiliation":[{"name":"Luxembourg Centre for Systems Biomedicine, University of Luxembourg , Esch-sur-Alzette Luxembourg"}]},{"given":"Zhen","family":"Chen","sequence":"additional","affiliation":[{"name":"Collaborative Innovation Center of Henan Grain Crops, Henan Agricultural University , Zhengzhou 450046, China"}]},{"given":"Wenguang","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Biology, Institute of Molecular Systems Biology , ETH Zurich, Switzerland"}]},{"given":"Patrick G A","family":"Pedrioli","sequence":"additional","affiliation":[{"name":"Department of Biology, Institute of Molecular Systems Biology , ETH Zurich, Switzerland"}]},{"given":"Anthony W","family":"Purcell","sequence":"additional","affiliation":[{"name":"Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University , Melbourne, VIC 3800, Australia"}]},{"given":"Mar\u00eda Rodr\u00edguez","family":"Mart\u00ednez","sequence":"additional","affiliation":[{"name":"IBM Research Europe , Zurich, Switzerland"}]},{"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 Molecular Biology, Monash University , Melbourne, VIC 3800, Australia"},{"name":"Monash Data Futures Institute, Monash University , Melbourne, VIC 3800, Australia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8872-0269","authenticated-orcid":false,"given":"Matteo","family":"Manica","sequence":"additional","affiliation":[{"name":"IBM Research Europe , Zurich, Switzerland"}]},{"given":"Ruedi","family":"Aebersold","sequence":"additional","affiliation":[{"name":"Department of Biology, Institute of Molecular Systems Biology , ETH Zurich, Switzerland"},{"name":"Faculty of Science, University of Zurich , Switzerland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1847-754X","authenticated-orcid":false,"given":"Chen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biology, Institute of Molecular Systems Biology , ETH Zurich, Switzerland"},{"name":"Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University , Melbourne, VIC 3800, 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