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While a number of computational methods to assess the effects of variants on protein\u2013protein binding affinity have been proposed, they are in general limited to the analysis of single point mutations and have been shown to perform poorly on independent test sets. Here, we present mmCSM-PPI, a scalable and effective machine learning model for accurately assessing changes in protein\u2013protein binding affinity caused by single and multiple missense mutations. We expanded our well-established graph-based signatures in order to capture physicochemical and geometrical properties of multiple wild-type residue environments and integrated them with substitution scores and dynamics terms from normal mode analysis. mmCSM-PPI was able to achieve a Pearson's correlation of up to 0.75 (RMSE = 1.64 kcal\/mol) under 10-fold cross-validation and 0.70 (RMSE = 2.06 kcal\/mol) on a non-redundant blind test, outperforming existing methods. Our method is freely available as a user-friendly and easy-to-use web server and API at http:\/\/biosig.unimelb.edu.au\/mmcsm_ppi.<\/jats:p>","DOI":"10.1093\/nar\/gkab273","type":"journal-article","created":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T21:01:58Z","timestamp":1618606918000},"page":"W417-W424","source":"Crossref","is-referenced-by-count":81,"title":["mmCSM-PPI: predicting the effects of multiple point mutations on protein\u2013protein interactions"],"prefix":"10.1093","volume":"49","author":[{"given":"Carlos H M","family":"Rodrigues","sequence":"first","affiliation":[{"name":"Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia"},{"name":"Structural Biology and Bioinformatics, Department of Biochemistry and Pharmacology, University of Melbourne, Melbourne, Victoria, Australia"},{"name":"Systems and Computational Biology, Bio21 Institute, University of Melbourne, Melbourne, Victoria, Australia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3004-2119","authenticated-orcid":false,"given":"Douglas E V","family":"Pires","sequence":"additional","affiliation":[{"name":"Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia"},{"name":"Structural Biology and Bioinformatics, Department of Biochemistry and Pharmacology, University of Melbourne, Melbourne, Victoria, Australia"},{"name":"Systems and Computational Biology, Bio21 Institute, University of Melbourne, Melbourne, Victoria, Australia"},{"name":"School of Computing and Information Systems, University of Melbourne, Melbourne, Victoria, Australia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2948-2413","authenticated-orcid":false,"given":"David B","family":"Ascher","sequence":"additional","affiliation":[{"name":"Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia"},{"name":"Structural Biology and Bioinformatics, Department of Biochemistry and Pharmacology, University of Melbourne, Melbourne, Victoria, Australia"},{"name":"Systems and Computational Biology, Bio21 Institute, University of Melbourne, Melbourne, Victoria, Australia"},{"name":"Department of Biochemistry, University of Cambridge, Cambridge, UK"}]}],"member":"286","published-online":{"date-parts":[[2021,4,24]]},"reference":[{"key":"2021070812012277900_B1","doi-asserted-by":"crossref","first-page":"6959","DOI":"10.1073\/pnas.0708078105","article-title":"Estimating the size of the human interactome","volume":"105","author":"Stumpf","year":"2008","journal-title":"Proc. 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