{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T15:26:30Z","timestamp":1758122790191},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,2,15]]},"abstract":"<jats:p>Motivation: A number of statistical phylogenetic methods have been developed to infer conserved functional sites or regions in proteins. Many methods, e.g. Rate4Site, apply the standard phylogenetic models to infer site-specific substitution rates and totally ignore the spatial correlation of substitution rates in protein tertiary structures, which may reduce their power to identify conserved functional patches in protein tertiary structures when the sequences used in the analysis are highly similar. The 3D sliding window method has been proposed to infer conserved functional patches in protein tertiary structures, but the window size, which reflects the strength of the spatial correlation, must be predefined and is not inferred from data. We recently developed GP4Rate to solve these problems under the Bayesian framework. Unfortunately, GP4Rate is computationally slow. Here, we present an intuitive web server, FuncPatch, to perform a fast approximate Bayesian inference of conserved functional patches in protein tertiary structures.<\/jats:p><jats:p>Results: Both simulations and four case studies based on empirical data suggest that FuncPatch is a good approximation to GP4Rate. However, FuncPatch is orders of magnitudes faster than GP4Rate. In addition, simulations suggest that FuncPatch is potentially a useful tool complementary to Rate4Site, but the 3D sliding window method is less powerful than FuncPatch and Rate4Site. The functional patches predicted by FuncPatch in the four case studies are supported by experimental evidence, which corroborates the usefulness of FuncPatch.<\/jats:p><jats:p>Availability and implementation: The software FuncPatch is freely available at the web site, http:\/\/info.mcmaster.ca\/yifei\/FuncPatch<\/jats:p><jats:p>Contact: \u00a0golding@mcmaster.ca<\/jats:p><jats:p>Supplementary information: \u00a0Supplementary Data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btu673","type":"journal-article","created":{"date-parts":[[2014,10,17]],"date-time":"2014-10-17T05:05:29Z","timestamp":1413522329000},"page":"523-531","source":"Crossref","is-referenced-by-count":22,"title":["FuncPatch: a web server for the fast Bayesian inference of conserved functional patches in protein 3D structures"],"prefix":"10.1093","volume":"31","author":[{"given":"Yi-Fei","family":"Huang","sequence":"first","affiliation":[{"name":"1Department of Biology, McMaster University, Hamilton, ON L8S4K1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G. Brian","family":"Golding","sequence":"additional","affiliation":[{"name":"1Department of Biology, McMaster University, Hamilton, ON L8S4K1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2014,10,15]]},"reference":[{"key":"2023020108564459900_btu673-B1","doi-asserted-by":"crossref","first-page":"W529","DOI":"10.1093\/nar\/gkq399","article-title":"ConSurf 2010: calculating evolutionary conservation in sequence and structure of proteins and nucleic acids","volume":"38","author":"Ashkenazy","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"2023020108564459900_btu673-B2","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2001-2-8-reviews3010","article-title":"The Smads","volume":"2","author":"Attisano","year":"2001","journal-title":"Genome Biol."},{"key":"2023020108564459900_btu673-B3","doi-asserted-by":"crossref","first-page":"3477","DOI":"10.1093\/nar\/gkq046","article-title":"Structure of Smad1 MH1\/DNA complex reveals distinctive rearrangements of BMP and TGF-\u03b2 effectors","volume":"38","author":"Baburajendran","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"2023020108564459900_btu673-B4","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1007\/s00239-004-0223-4","article-title":"Tertiary windowing to detect positive diversifying selection","volume":"60","author":"Berglund","year":"2005","journal-title":"J. Mol. Evol."},{"key":"2023020108564459900_btu673-B5","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/S0092-8674(00)80351-7","article-title":"Activation mechanism of the MAP kinase ERK2 by dual phosphorylation","volume":"90","author":"Canagarajah","year":"1997","journal-title":"Cell"},{"key":"2023020108564459900_btu673-B6","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1093\/bioinformatics\/btm270","article-title":"Predicting functionally important residues from sequence conservation","volume":"23","author":"Capra","year":"2007","journal-title":"Bioinformatics"},{"key":"2023020108564459900_btu673-B7","first-page":"6","article-title":"Enzyme evolution explained (sort of)","volume":"2000","author":"Dean","year":"2000","journal-title":"Pac. Symp. Biocomput."},{"key":"2023020108564459900_btu673-B8","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1186\/1471-2105-7-188","article-title":"Bio++: a set of C++ libraries for sequence analysis, phylogenetics, molecular evolution and population genetics","volume":"7","author":"Dutheil","year":"2006","journal-title":"BMC Bioinformatics"},{"key":"2023020108564459900_btu673-B9","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1093\/nar\/gkh340","article-title":"MUSCLE: multiple sequence alignment with high accuracy and high throughput","volume":"32","author":"Edgar","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"2023020108564459900_btu673-B10","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1007\/BF01734359","article-title":"Evolutionary trees from DNA sequences: a maximum likelihood approach","volume":"17","author":"Felsenstein","year":"1981","journal-title":"J. Mol. Evol."},{"key":"2023020108564459900_btu673-B11","first-page":"164","article-title":"PHYLIP\u2014phylogeny inference package (version 3.2)","volume":"5","author":"Felsenstein","year":"1989","journal-title":"Cladistics"},{"key":"2023020108564459900_btu673-B12","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1007\/BF03401678","article-title":"A genetic approach to mapping the p53 binding site in the MDM2 protein","volume":"3","author":"Freedman","year":"1997","journal-title":"Mol. Med."},{"key":"2023020108564459900_btu673-B13","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1093\/bioinformatics\/19.1.163","article-title":"ConSurf: identification of functional regions in proteins by surface-mapping of phylogenetic information","volume":"19","author":"Glaser","year":"2003","journal-title":"Bioinformatics"},{"key":"2023020108564459900_btu673-B14","doi-asserted-by":"crossref","first-page":"D323","DOI":"10.1093\/nar\/gkn822","article-title":"The ConSurf-DB: pre-calculated evolutionary conservation profiles of protein structures","volume":"37","author":"Goldenberg","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2023020108564459900_btu673-B15","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1093\/oxfordjournals.molbev.a026080","article-title":"Statistical methods for testing functional divergence after gene duplication","volume":"16","author":"Gu","year":"1999","journal-title":"Mol. Biol. Evol."},{"key":"2023020108564459900_btu673-B16","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1093\/molbev\/mst097","article-title":"Bio++: efficient extensible libraries and tools for computational molecular evolution","volume":"30","author":"Gueguen","year":"2013","journal-title":"Mol. Biol. Evol."},{"key":"2023020108564459900_btu673-B17","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1080\/10635150390235520","article-title":"A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood","volume":"52","author":"Guindon","year":"2003","journal-title":"Syst. Biol."},{"key":"2023020108564459900_btu673-B18","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1093\/bioinformatics\/btr635","article-title":"Inferring sequence regions under functional divergence in duplicate genes","volume":"28","author":"Huang","year":"2012","journal-title":"Bioinformatics"},{"key":"2023020108564459900_btu673-B19","doi-asserted-by":"crossref","first-page":"e1003429","DOI":"10.1371\/journal.pcbi.1003429","article-title":"Phylogenetic Gaussian process model for the inference of functionally important regions in protein tertiary structures","volume":"10","author":"Huang","year":"2014","journal-title":"PLoS Comput. Biol."},{"key":"2023020108564459900_btu673-B20","first-page":"275","article-title":"The rapid generation of mutation data matrices from protein sequences","volume":"8","author":"Jones","year":"1992","journal-title":"Comput. Appl. Biosci."},{"key":"2023020108564459900_btu673-B21","doi-asserted-by":"crossref","first-page":"14512","DOI":"10.1073\/pnas.251526398","article-title":"A likelihood ratio test for evolutionary rate shifts and functional divergence among proteins","volume":"98","author":"Knudsen","year":"2001","journal-title":"Proc. Natl Acad. Sci. U S A"},{"key":"2023020108564459900_btu673-B22","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1006\/jmbi.2001.4540","article-title":"Three-dimensional cluster analysis identifies interfaces and functional residue clusters in proteins","volume":"307","author":"Landgraf","year":"2001","journal-title":"J. Mol. Biol."},{"key":"2023020108564459900_btu673-B23","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1006\/jmbi.2001.5327","article-title":"Structural clusters of evolutionary trace residues are statistically significant and common in proteins","volume":"316","author":"Madabushi","year":"2002","journal-title":"J. Mol. Biol."},{"key":"2023020108564459900_btu673-B24","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1093\/molbev\/msh194","article-title":"Comparison of site-specific rate-inference methods for protein sequences: empirical Bayesian methods are superior","volume":"21","author":"Mayrose","year":"2004","journal-title":"Mol. Biol. Evol."},{"key":"2023020108564459900_btu673-B25","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/381335a0","article-title":"X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death","volume":"381","author":"Muchmore","year":"1996","journal-title":"Nature"},{"key":"2023020108564459900_btu673-B26","doi-asserted-by":"crossref","first-page":"i328","DOI":"10.1093\/bioinformatics\/bti1023","article-title":"In silico identification of functional regions in proteins","volume":"21","author":"Nimrod","year":"2005","journal-title":"Bioinformatics"},{"key":"2023020108564459900_btu673-B27","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1110\/ps.03465504","article-title":"Prediction of functional sites by analysis of sequence and structure conservation","volume":"13","author":"Panchenko","year":"2004","journal-title":"Protein Sci."},{"key":"2023020108564459900_btu673-B28","doi-asserted-by":"crossref","DOI":"10.7551\/mitpress\/3206.001.0001","volume-title":"Gaussian Processes for Machine Learning","author":"Rasmussen","year":"2005","edition":"1st edn"},{"key":"2023020108564459900_btu673-B29","first-page":"406","article-title":"The neighbor-joining method: a new method for reconstructing phylogenetic trees","volume":"4","author":"Saitou","year":"1987","journal-title":"Mol. Biol. Evol."},{"key":"2023020108564459900_btu673-B30","doi-asserted-by":"crossref","first-page":"D13","DOI":"10.1093\/nar\/gkr1184","article-title":"Database resources of the National Center for Biotechnology Information","volume":"40","author":"Sayers","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2023020108564459900_btu673-B31","doi-asserted-by":"crossref","first-page":"41430","DOI":"10.1074\/jbc.M005727200","article-title":"Calmodulin differentially modulates Smad1 and Smad2 signaling","volume":"275","author":"Scherer","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2023020108564459900_btu673-B32","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1096\/fasebj.9.9.7601337","article-title":"The MAPK signaling cascade","volume":"9","author":"Seger","year":"1995","journal-title":"FASEB J."},{"key":"2023020108564459900_btu673-B33","doi-asserted-by":"crossref","first-page":"3940","DOI":"10.1093\/bioinformatics\/bti623","article-title":"ROCR: visualizing classifier performance in R","volume":"21","author":"Sing","year":"2005","journal-title":"Bioinformatics"},{"key":"2023020108564459900_btu673-B34","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1101\/gr.361602","article-title":"The Bioperl toolkit: Perl modules for the life sciences","volume":"12","author":"Stajich","year":"2002","journal-title":"Genome Res."},{"key":"2023020108564459900_btu673-B35","doi-asserted-by":"crossref","first-page":"2352","DOI":"10.1093\/molbev\/msh249","article-title":"Three-dimensional window analysis for detecting positive selection at structural regions of proteins","volume":"21","author":"Suzuki","year":"2004","journal-title":"Mol. Biol. Evol."},{"key":"2023020108564459900_btu673-B36","doi-asserted-by":"crossref","first-page":"6141","DOI":"10.1021\/ja8071995","article-title":"How mitogen-activated protein kinases recognize and phosphorylate their targets: a QM\/MM study","volume":"131","author":"Turjanski","year":"2009","journal-title":"J. Am. Chem. Soc."},{"key":"2023020108564459900_btu673-B37","first-page":"73","article-title":"Sparse log Gaussian processes via MCMC for spatial epidemiology","volume":"1","author":"Vanhatalo","year":"2007","journal-title":"J. Mach. Learn. Res. \u2013 Proc. Track"},{"key":"2023020108564459900_btu673-B38","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1002\/sim.3895","article-title":"Approximate inference for disease mapping with sparse Gaussian processes","volume":"29","author":"Vanhatalo","year":"2010","journal-title":"Stat. Med."},{"key":"2023020108564459900_btu673-B39","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/S0014-5793(99)00555-4","article-title":"Structural and biochemical analysis of RAS-effector signaling via RaLGDS","volume":"451","author":"Vetter","year":"1999","journal-title":"FEBS Lett."},{"key":"2023020108564459900_btu673-B40","doi-asserted-by":"crossref","DOI":"10.1201\/9780429258794","volume-title":"The Biology of Cancer","author":"Weinberg","year":"2013"},{"key":"2023020108564459900_btu673-B41","doi-asserted-by":"crossref","DOI":"10.1038\/npre.2007.50.1","article-title":"Fast and scriptable molecular graphics in web browsers without Java3D","author":"Willighagen","year":"2007","journal-title":"Nature Precedings"},{"key":"2023020108564459900_btu673-B42","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1007\/BF00160154","article-title":"Maximum likelihood phylogenetic estimation from DNA sequences with variable rates over sites: approximate methods","volume":"39","author":"Yang","year":"1994","journal-title":"J. Mol. Evol."},{"key":"2023020108564459900_btu673-B43","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/367704a0","article-title":"Atomic structure of the map kinase ERK2 at 2.3 a resolution","volume":"367","author":"Zhang","year":"1994","journal-title":"Nature"},{"key":"2023020108564459900_btu673-B44","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1145\/279232.279236","article-title":"Algorithm 778: L-BFGS-B: Fortran subroutines for large-scale bound-constrained optimization","volume":"23","author":"Zhu","year":"1997","journal-title":"ACM Trans. Math. Softw."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/31\/4\/523\/49011146\/bioinformatics_31_4_523.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/31\/4\/523\/49011146\/bioinformatics_31_4_523.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T01:02:44Z","timestamp":1717462964000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/31\/4\/523\/2748177"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,10,15]]},"references-count":44,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2015,2,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btu673","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,10,15]]}}}