{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:05:49Z","timestamp":1760238349925,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T00:00:00Z","timestamp":1658880000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006312","name":"BrightFocus Foundation","doi-asserted-by":"publisher","award":["A2020118F","A2020161S","1P30AG072946-01","AG068331","GM138636","2019-AARG-644082"],"award-info":[{"award-number":["A2020118F","A2020161S","1P30AG072946-01","AG068331","GM138636","2019-AARG-644082"]}],"id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["A2020118F","A2020161S","1P30AG072946-01","AG068331","GM138636","2019-AARG-644082"],"award-info":[{"award-number":["A2020118F","A2020161S","1P30AG072946-01","AG068331","GM138636","2019-AARG-644082"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer\u2019s Association","doi-asserted-by":"publisher","award":["A2020118F","A2020161S","1P30AG072946-01","AG068331","GM138636","2019-AARG-644082"],"award-info":[{"award-number":["A2020118F","A2020161S","1P30AG072946-01","AG068331","GM138636","2019-AARG-644082"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Protein\u2013protein functional interactions arise from either transitory or permanent biomolecular associations and often lead to the coevolution of the interacting residues. Although mutual information has traditionally been used to identify coevolving residues within the same protein, its application between coevolving proteins remains largely uncharacterized. Therefore, we developed the Protein Interactions Calculator (PIC) to efficiently identify coevolving residues between two protein sequences using mutual information. We verified the algorithm using 2102 known human protein interactions and 233 known bacterial protein interactions, with a respective 1975 and 252 non-interacting protein controls. The average PIC score for known human protein interactions was 4.5 times higher than non-interacting proteins (p = 1.03 \u00d7 10\u2212108) and 1.94 times higher in bacteria (p = 1.22 \u00d7 10\u221235). We then used the PIC scores to determine the probability that two proteins interact. Using those probabilities, we paired 37 Alzheimer\u2019s disease-associated proteins with 8608 other proteins and determined the likelihood that each pair interacts, which we report through a web interface. The PIC had significantly higher sensitivity and residue-specific resolution not available in other algorithms. Therefore, we propose that the PIC can be used to prioritize potential protein interactions, which can lead to a better understanding of biological processes and additional therapeutic targets belonging to protein interaction groups.<\/jats:p>","DOI":"10.3390\/genes13081346","type":"journal-article","created":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T21:11:05Z","timestamp":1658956265000},"page":"1346","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Web-Based Protein Interactions Calculator Identifies Likely Proteome Coevolution with Alzheimer\u2019s Disease-Associated Proteins"],"prefix":"10.3390","volume":"13","author":[{"given":"Katrisa M.","family":"Ward","sequence":"first","affiliation":[{"name":"Department of Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8235-4440","authenticated-orcid":false,"given":"Brandon D.","family":"Pickett","sequence":"additional","affiliation":[{"name":"Department of Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark T. W.","family":"Ebbert","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA"},{"name":"Division of Biomedical Informatics, Department of Internal Medicine, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Neuroscience, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8641-2468","authenticated-orcid":false,"given":"John S. K.","family":"Kauwe","sequence":"additional","affiliation":[{"name":"Department of Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5309-1570","authenticated-orcid":false,"given":"Justin B.","family":"Miller","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA"},{"name":"Division of Biomedical Informatics, Department of Internal Medicine, University of Kentucky, Lexington, KY 40506, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40506, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/s41586-020-2188-x","article-title":"A reference map of the human binary protein interactome","volume":"580","author":"Luck","year":"2020","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1038\/s41467-019-09177-y","article-title":"Network-based prediction of protein interactions","volume":"10","author":"Luck","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.tibs.2017.02.006","article-title":"Proteome-Scale Human Interactomics","volume":"42","author":"Luck","year":"2017","journal-title":"Trends Biochem Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s13195-017-0252-z","article-title":"Analyzing the genes related to Alzheimer\u2019s disease via a network and pathway-based approach","volume":"9","author":"Hu","year":"2017","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41588-018-0311-9","article-title":"Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer\u2019s disease risk","volume":"51","author":"Jansen","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"D808","DOI":"10.1093\/nar\/gks1094","article-title":"STRING v9. 1: Protein-protein interaction networks, with increased coverage and integration","volume":"41","author":"Franceschini","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"D412","DOI":"10.1093\/nar\/gkn760","article-title":"STRING 8\u2014a global view on proteins and their functional interactions in 630 organisms","volume":"37","author":"Jensen","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1093\/nar\/gkg034","article-title":"STRING: A database of predicted functional associations between proteins","volume":"31","author":"Jaeggi","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3442","DOI":"10.1093\/nar\/28.18.3442","article-title":"STRING: A web-server to retrieve and display the repeatedly occurring neighbourhood of a gene","volume":"28","author":"Snel","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"D561","DOI":"10.1093\/nar\/gkq973","article-title":"The STRING database in 2011: Functional interaction networks of proteins, globally integrated and scored","volume":"39","author":"Szklarczyk","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"D447","DOI":"10.1093\/nar\/gku1003","article-title":"STRING v10: Protein\u2013protein interaction networks, integrated over the tree of life","volume":"43","author":"Szklarczyk","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: Protein\u2013protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"D362","DOI":"10.1093\/nar\/gkw937","article-title":"The STRING database in 2017: Quality-controlled protein\u2013protein association networks, made broadly accessible","volume":"45","author":"Szklarczyk","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"D358","DOI":"10.1093\/nar\/gkl825","article-title":"STRING 7\u2014recent developments in the integration and prediction of protein interactions","volume":"35","author":"Jensen","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_15","first-page":"D433","article-title":"STRING: Known and predicted protein\u2013protein associations, integrated and transferred across organisms","volume":"33","author":"Jensen","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1093\/bioinformatics\/btv696","article-title":"SVD-phy: Improved prediction of protein functional associations through singular value decomposition of phylogenetic profiles","volume":"32","author":"Franceschini","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Fahey, M.E., Bennett, M.J., Mahon, C., J\u00e4ger, S., Pache, L., Kumar, D., Shapiro, A., Rao, K., Chanda, S.K., and Craik, C.S. (2011). GPS-Prot: A web-based visualization platform for integrating host-pathogen interaction data. BMC Bioinform., 12.","DOI":"10.1186\/1471-2105-12-298"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Orii, N., and Ganapathiraju, M.K. (2012). Wiki-pi: A web-server of annotated human protein-protein interactions to aid in discovery of protein function. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049029"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/msb4100203","article-title":"Accurate prediction of protein\u2013protein interactions from sequence alignments using a Bayesian method","volume":"4","author":"Burger","year":"2008","journal-title":"Mol. Syst. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1073\/pnas.0805923106","article-title":"Identification of direct residue contacts in protein\u2013protein interaction by message passing","volume":"106","author":"Weigt","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Marks, D.S., Colwell, L.J., Sheridan, R., Hopf, T.A., Pagnani, A., Zecchina, R., and Sander, C. (2011). Protein 3D structure computed from evolutionary sequence variation. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0028766"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1534\/genetics.113.155861","article-title":"Predicting functionally informative mutations in Escherichia coli BamA using evolutionary covariance analysis","volume":"195","author":"Dwyer","year":"2013","journal-title":"Genetics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3054","DOI":"10.1093\/molbev\/msw188","article-title":"Connecting the sequence-space of bacterial signaling proteins to phenotypes using coevolutionary landscapes","volume":"33","author":"Cheng","year":"2016","journal-title":"Mol. Biol. Evol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"E1293","DOI":"10.1073\/pnas.1111471108","article-title":"Direct-coupling analysis of residue coevolution captures native contacts across many protein families","volume":"108","author":"Morcos","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Baldassi, C., Zamparo, M., Feinauer, C., Procaccini, A., Zecchina, R., Weigt, M., and Pagnani, A. (2014). Fast and accurate multivariate Gaussian modeling of protein families: Predicting residue contacts and protein-interaction partners. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0092721"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e03430","DOI":"10.7554\/eLife.03430","article-title":"Sequence co-evolution gives 3D contacts and structures of protein complexes","volume":"3","author":"Hopf","year":"2014","journal-title":"Elife"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"12180","DOI":"10.1073\/pnas.1606762113","article-title":"Inferring interaction partners from protein sequences","volume":"113","author":"Bitbol","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Bitbol, A.-F. (2018). Inferring interaction partners from protein sequences using mutual information. PLOS Comput. Biol., 14.","DOI":"10.1101\/378042"},{"key":"ref_30","unstructured":"Cover, T.M. (1999). Elements of Information Theory, John Wiley & Sons."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"W307","DOI":"10.1093\/nar\/gkx336","article-title":"BIS2Analyzer: A server for co-evolution analysis of conserved protein families","volume":"45","author":"Oteri","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1093\/bioinformatics\/btm584","article-title":"An integrated system for studying residue coevolution in proteins","volume":"24","author":"Yip","year":"2008","journal-title":"Bioinformatics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1093\/bioinformatics\/btp335","article-title":"InterMap3D: Predicting and visualizing co-evolving protein residues","volume":"25","author":"Roque","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"W323","DOI":"10.1093\/nar\/gky419","article-title":"MISTIC2: Comprehensive server to study coevolution in protein families","volume":"46","author":"Colell","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1007\/BF00486096","article-title":"An improved method for determining codon variability in a gene and its application to the rate of fixation of mutations in evolution","volume":"4","author":"Fitch","year":"1970","journal-title":"Biochem. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3128","DOI":"10.1093\/bioinformatics\/btu500","article-title":"CCMpred\u2014fast and precise prediction of protein residue\u2013residue contacts from correlated mutations","volume":"30","author":"Seemayer","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1002\/prot.340180402","article-title":"Correlated mutations and residue contacts in proteins","volume":"18","author":"Sander","year":"1994","journal-title":"Proteins Struct. Funct. Bioinform."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1093\/protein\/7.3.349","article-title":"Can three-dimensional contacts in protein structures be predicted by analysis of correlated mutations?","volume":"7","author":"Shindyalov","year":"1994","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1186\/1471-2156-16-S2-S2","article-title":"Genetic analysis, structural modeling, and direct coupling analysis suggest a mechanism for phosphate signaling in Escherichia coli","volume":"16","author":"Gardner","year":"2015","journal-title":"BMC Genet."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Morley, S.A., Peralta-Castro, A., Brieba, L.G., Miller, J., Ong, K.L., Ridge, P.G., Oliphant, A., Aldous, S., and Nielsen, B.L. (2019). Arabidopsis thaliana organelles mimic the T7 phage DNA replisome with specific interactions between Twinkle protein and DNA polymerases Pol1A and Pol1B. BMC Plant Biol., 19.","DOI":"10.1186\/s12870-019-1854-3"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Ding, Y., Tang, J., and Guo, F. (2016). Predicting protein-protein interactions via multivariate mutual information of protein sequences. BMC Bioinform., 17.","DOI":"10.1186\/s12859-016-1253-9"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1093\/bioinformatics\/btm604","article-title":"Mutual information without the influence of phylogeny or entropy dramatically improves residue contact prediction","volume":"24","author":"Dunn","year":"2008","journal-title":"Bioinformatics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4116","DOI":"10.1093\/bioinformatics\/bti671","article-title":"Using information theory to search for co-evolving residues in proteins","volume":"21","author":"Martin","year":"2005","journal-title":"Bioinformatics"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"D733","DOI":"10.1093\/nar\/gkv1189","article-title":"Reference sequence (RefSeq) database at NCBI: Current status, taxonomic expansion, and functional annotation","volume":"44","author":"Wright","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6614","DOI":"10.1093\/nar\/gkw569","article-title":"NCBI prokaryotic genome annotation pipeline","volume":"44","author":"Tatusova","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"D571","DOI":"10.1093\/nar\/gku1207","article-title":"NCBI viral genomes resource","volume":"43","author":"Brister","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1002\/pro.3290","article-title":"Clustal Omega for making accurate alignments of many protein sequences","volume":"27","author":"Sievers","year":"2018","journal-title":"Protein Sci"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/S1474-4422(19)30435-1","article-title":"Interpretation of risk loci from genome-wide association studies of Alzheimer\u2019s disease","volume":"19","author":"Andrews","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e241","DOI":"10.1016\/j.neurobiolaging.2019.02.022","article-title":"Identification of genetic heterogeneity of Alzheimer\u2019s disease across age","volume":"84","author":"Lo","year":"2019","journal-title":"Neurobiol. Aging"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"D8","DOI":"10.1093\/nar\/gkx1095","article-title":"Database resources of the National Center for Biotechnology Information","volume":"46","author":"Coordinators","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"D756","DOI":"10.1093\/nar\/gkt1114","article-title":"RefSeq: An update on mammalian reference sequences","volume":"42","author":"Pruitt","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Douam, F., Fusil, F., Enguehard, M., Dib, L., Nadalin, F., Schwaller, L., Hrebikova, G., Mancip, J., Mailly, L., and Montserret, R. (2018). A protein coevolution method uncovers critical features of the Hepatitis C Virus fusion mechanism. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1006908"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1016\/j.str.2019.05.001","article-title":"Interplay of protein disorder in retinoic acid receptor heterodimer and its corepressor regulates gene expression","volume":"27","author":"Cordeiro","year":"2019","journal-title":"Structure"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Astl, L., and Verkhivker, G.M. (2019). Data-driven computational analysis of allosteric proteins by exploring protein dynamics, residue coevolution and residue interaction networks. Biochim. Et Biophys. Acta (BBA)-Gen. Subj., S0304-4165(19)30179-5.","DOI":"10.1016\/j.bbagen.2019.07.008"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"14575","DOI":"10.1096\/fj.201901624RR","article-title":"Identification of novel proteolytically inactive mutations in coronavirus 3C-like protease using a combined approach","volume":"33","author":"Zhou","year":"2019","journal-title":"FASEB J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"D439","DOI":"10.1093\/nar\/gkab1061","article-title":"AlphaFold Protein Structure Database: Massively expanding the structural coverage of protein-sequence space with high-accuracy models","volume":"50","author":"Varadi","year":"2022","journal-title":"Nucleic Acids Res."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/8\/1346\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:57:30Z","timestamp":1760140650000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/8\/1346"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,27]]},"references-count":57,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["genes13081346"],"URL":"https:\/\/doi.org\/10.3390\/genes13081346","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2022,7,27]]}}}