Advances in In-silico B-cell Epitope Prediction

Author(s): Pingping Sun, Sijia Guo, Jiahang Sun, Liming Tan, Chang Lu, Zhiqiang Ma*.

Journal Name: Current Topics in Medicinal Chemistry

Volume 19 , Issue 2 , 2019

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Graphical Abstract:


Identification of B-cell epitopes in target antigens is one of the most crucial steps for epitopebased vaccine development, immunodiagnostic tests, antibody production, and disease diagnosis and therapy. Experimental methods for B-cell epitope mapping are time consuming, costly and labor intensive; in the meantime, various in-silico methods are proposed to predict both linear and conformational B-cell epitopes. The accurate identification of B-cell epitopes presents major challenges for immunoinformaticians. In this paper, we have comprehensively reviewed in-silico methods for B-cell epitope identification. The aim of this review is to stimulate the development of better tools which could improve the identification of B-cell epitopes, and further for the development of therapeutic antibodies and diagnostic tools.

Keywords: Epitope prediction, Linear epitope, Conformational epitope, BCR, B-cell, Epitope.

Peters, B.; Sidney, J.; Bourne, P.; Bui, H.H.; Buus, S.; Doh, G.; Fleri, W.; Kronenberg, M.; Kubo, R.; Lund, O.; Nemazee, D.; Ponomarenko, J.V.; Sathiamurthy, M.; Schoenberger, S.P.; Stewart, S.; Surko, P.; Way, S.; Wilson, S.; Sette, A. The design and implementation of the immune epitope database and analysis resource. Immunogenetics, 2005, 57(5), 326-336.
[] [PMID: 15895191]
Van Regenmortel, M.H. The concept and operational definition of protein epitopes. Philos. Trans. R. Soc. Lond. B Biol. Sci., 1989, 323(1217), 451-466.
[] [PMID: 2474169]
Ponomarenko, J.; Bui, H.H.; Li, W.; Fusseder, N.; Bourne, P.E.; Sette, A.; Peters, B. ElliPro: A new structure-based tool for the prediction of antibody epitopes. BMC Bioinformatics, 2008, 9, 514.
[] [PMID: 19055730]
Smith, D.J.; Taubman, M.A.; Holmberg, C.F.; Eastcott, J.; King, W.F.; Ali-Salaam, P. Antigenicity and immunogenicity of a synthetic peptide derived from a glucan-binding domain of mutans streptococcal glucosyltransferase. Infect. Immun., 1993, 61(7), 2899-2905.
[PMID: 8514393]
Barlow, D.J.; Edwards, M.S.; Thornton, J.M. Continuous and discontinuous protein antigenic determinants. Nature, 1986, 322(6081), 747-748.
[] [PMID: 2427953]
Castelli, M.; Cappelletti, F.; Diotti, R.A.; Sautto, G.; Criscuolo, E.; Dal Peraro, M.; Clementi, N. Peptide-based vaccinology: experimental and computational approaches to target hypervariable viruses through the fine characterization of protective epitopes recognized by monoclonal antibodies and the identification of T-cell-activating peptides. Clin. Dev. Immunol., 2013, 2013, 521231.
[] [PMID: 23878584]
Rux, J.J.; Burnett, R.M. Type-specific epitope locations revealed by X-ray crystallographic study of adenovirus type 5 hexon. Mol. Ther., 2000, 1(1), 18-30.
[ 10.1006/mthe.1999.0001] [PMID: 10933908]
Mayer, M.; Meyer, B. Group epitope mapping by saturation transfer difference NMR to identify segments of a ligand in direct contact with a protein receptor. J. Am. Chem. Soc., 2001, 123(25), 6108-6117.
[] [PMID: 11414845]
Hopp, T.P.; Woods, K.R. Prediction of protein antigenic determinants from amino acid sequences. Proc. Natl. Acad. Sci. USA, 1981, 78(6), 3824-3828.
[] [PMID: 6167991]
Westhof, E.; Altschuh, D.; Moras, D.; Bloomer, A.C.; Mondragon, A.; Klug, A.; Van Regenmortel, M.H. Correlation between segmental mobility and the location of antigenic determinants in proteins. Nature, 1984, 311(5982), 123-126.
[ 10.1038/311123a0] [PMID: 6206398]
Emini, E.A.; Hughes, J.V.; Perlow, D.S.; Boger, J. Induction of hepatitis A virus-neutralizing antibody by a virus-specific synthetic peptide. J. Virol., 1985, 55(3), 836-839.
[PMID: 2991600]
Karplus, P.A.S.G. Prediction of chain flexibility in proteins - a tool for the selection of peptide antigens. Naturwissenschaften, 1985, 72, 2.
Welling, G.W.; Weijer, W.J.; van der Zee, R.; Welling-Wester, S. Prediction of sequential antigenic regions in proteins. FEBS Lett., 1985, 188(2), 215-218.
[] [PMID: 2411595]
Parker, J.M.; Guo, D.; Hodges, R.S. New hydrophilicity scale derived from high-performance liquid chromatography peptide retention data: correlation of predicted surface residues with antigenicity and X-ray-derived accessible sites. Biochemistry, 1986, 25(19), 5425-5432.
[] [PMID: 2430611]
Thornton, J.M.; Edwards, M.S.; Taylor, W.R.; Barlow, D.J. Location of ‘continuous’ antigenic determinants in the protruding regions of proteins. EMBO J., 1986, 5(2), 409-413.
[] [PMID: 2423325]
Jameson, B.A.; Wolf, H. The antigenic index: a novel algorithm for predicting antigenic determinants. Comput. Appl. Biosci., 1988, 4(1), 181-186.
[PMID: 2454713]
Pellequer, J.L.; Westhof, E.; Van Regenmortel, M.H. Correlation between the location of antigenic sites and the prediction of turns in proteins. Immunol. Lett., 1993, 36(1), 83-99.
[] [PMID: 7688347]
Alix, A.J. Predictive estimation of protein linear epitopes by using the program PEOPLE. Vaccine, 1999, 18(3-4), 311-314.
[] [PMID: 10506656]
Odorico, M.; Pellequer, J.L. BEPITOPE: Predicting the location of continuous epitopes and patterns in proteins. J. Mol. Recognit., 2003, 16(1), 20-22.
[] [PMID: 12557235]
Saha, S.; Raghava, G.P.S. BcePred:prediction B-cell epitopes in antigenic sequences using physico-chemical properties. In: Artificial Immune Systems, 2004, 197-204.
Chang, H.T.; Liu, C.H.; Pai, T.W. Estimation and extraction of B-cell linear epitopes predicted by mathematical morphology approaches. J. Mol. Recognit., 2008, 21(6), 431-441.
[] [PMID: 18680207]
Biqing li L-LZ, Le-Le Hu, Kai-Yan Feng, Guo-Hua Huang and Lei Chen Prediction of Linear B-Cell Epitopes with mRMR feature selection and analysis. Curr. Bioinform., 2015, 11(999), 1-1.
Blythe, M.J.; Flower, D.R. Benchmarking B cell epitope prediction: Underperformance of existing methods. Protein Sci., 2005, 14(1), 246-248.
[] [PMID: 15576553]
Greenbaum, J.A.; Andersen, P.H.; Blythe, M.; Bui, H.H.; Cachau, R.E.; Crowe, J.; Davies, M.; Kolaskar, A.S.; Lund, O.; Morrison, S.; Mumey, B.; Ofran, Y.; Pellequer, J.L.; Pinilla, C.; Ponomarenko, J.V.; Raghava, G.P.; van Regenmortel, M.H.; Roggen, E.L.; Sette, A.; Schlessinger, A.; Sollner, J.; Zand, M.; Peters, B. Towards a consensus on datasets and evaluation metrics for developing B-cell epitope prediction tools. J. Mol. Recognit., 2007, 20(2), 75-82.
[] [PMID: 17205610]
Saha, S.; Raghava, G.P. Prediction of continuous B-cell epitopes in an antigen using recurrent neural network. Proteins, 2006, 65(1), 40-48.
[] [PMID: 16894596]
Larsen, J.E.; Lund, O.; Nielsen, M. Improved method for predicting linear B-cell epitopes. Immunome Res., 2006, 2, 2.
[] [PMID: 16635264]
Chen, J.; Liu, H.; Yang, J.; Chou, K.C. Prediction of linear B-cell epitopes using amino acid pair antigenicity scale. Amino Acids, 2007, 33(3), 423-428.
[] [PMID: 17252308]
El-Manzalawy, Y.; Dobbs, D.; Honavar, V. Predicting linear B-cell epitopes using string kernels. J. Mol. Recognit., 2008, 21(4), 243-255.
[] [PMID: 18496882]
El-Manzalawy, Y.; Dobbs, D.; Honavar, V. Predicting flexible length linear B-cell epitopes. Comput. Syst. Bioinformatics Conf., 2008, 7, 121-132.
[] [PMID: 19642274]
Sollner, J.; Grohmann, R.; Rapberger, R.; Perco, P.; Lukas, A.; Mayer, B. Analysis and prediction of protective continuous B-cell epitopes on pathogen proteins. Immunome Res., 2008, 4, 1.
[] [PMID: 18179690]
Sweredoski, M.J.; Baldi, P. COBEpro: A novel system for predicting continuous B-cell epitopes. Protein Eng. Des. Sel., 2009, 22(3), 113-120.
[] [PMID: 19074155]
Guedes, R.L.M.; Rodrigues, C.M.F.; Coatnoan, N.; Cosson, A.; Cadioli, F.A.; Garcia, H.A.; Gerber, A.L.; Machado, R.Z.; Minoprio, P.M.C.; Teixeira, M.M.G.; de Vasconcelos, A.T.R. A comparative in silico linear B-cell epitope prediction and characterization for South American and African Trypanosoma vivax strains. Genomics,, 2018, S0888-7543(18)30126-5.
[PMID: 29499243]
Wee, L.J.; Simarmata, D.; Kam, Y.W.; Ng, L.F.; Tong, J.C. SVM-based prediction of linear B-cell epitopes using bayes feature extraction. BMC Genomics, 2010, 11(Suppl. 4), S21.
[] [PMID: 21143805]
Wang, H.W.; Lin, Y.C.; Pai, T.W.; Chang, H.T. Prediction of B-cell linear epitopes with a combination of support vector machine classification and amino acid propensity identification. J. Biomed. Biotechnol., 2011, 2011, 432830.
[ 10.1155/2011/432830] [PMID: 21876642]
Wang, Y.; Wu, W.; Negre, N.N.; White, K.P.; Li, C.; Shah, P.K. Determinants of antigenicity and specificity in immune response for protein sequences. BMC Bioinformatics, 2011, 12, 251.
[] [PMID: 21693021]
Yao, B.; Zhang, L.; Liang, S.; Zhang, C. SVMTriP: a method to predict antigenic epitopes using support vector machine to integrate tri-peptide similarity and propensity. PLoS One, 2012, 7(9), e45152.
[] [PMID: 22984622]
Singh, H.; Ansari, H.R.; Raghava, G.P. Improved method for linear B-cell epitope prediction using antigen’s primary sequence. PLoS One, 2013, 8(5), e62216.
[] [PMID: 23667458]
Lian, Y.; Ge, M.; Pan, X.M. EPMLR: sequence-based linear B-cell epitope prediction method using multiple linear regression. BMC Bioinformatics, 2014, 15, 414.
[] [PMID: 25523327]
Honavar YE-MaV. Building classifier ensembles for B-cell epitope prediction. Methods Mol. Biol., 2014, 1184, 10.
El-Manzalawy, Y.H.V. A framework for developing epitope prediction tools. Proceedings of the First ACM International conference on bioinformatics and computational biology, 2010, pp. 660-662.
Saravanan, V.; Gautham, N. Harnessing computational biology for exact linear b-cell epitope prediction: A novel amino acid composition-based feature descriptor. OMICS, 2015, 19(10), 648-658.
[] [PMID: 26406767]
Jespersen, M.C.; Peters, B.; Nielsen, M.; Marcatili, P. BepiPred-2.0: Improving sequence-based B-cell epitope prediction using conformational epitopes. Nucleic Acids Res., 2017, 45(W1), W24-W29.
[] [PMID: 28472356]
Ansari, H.R.; Raghava, G.P. Identification of conformational B-cell epitopes in an antigen from its primary sequence. Immunome Res., 2010, 6, 6.
[] [PMID: 20961417]
Gao, J.; Faraggi, E.; Zhou, Y.; Ruan, J.; Kurgan, L. BEST: Improved prediction of B-cell epitopes from antigen sequences. PLoS One, 2012, 7(6), e40104.
[] [PMID: 22761950]
Zhang, W.; Niu, Y.; Xiong, Y.; Zhao, M.; Yu, R.; Liu, J. Computational prediction of conformational B-cell epitopes from antigen primary structures by ensemble learning. PLoS One, 2012, 7(8), e43575.
[] [PMID: 22927994]
Zhang, J.; Zhao, X.; Sun, P.; Gao, B.; Ma, Z. Conformational B-cell epitopes prediction from sequences using cost-sensitive ensemble classifiers and spatial clustering. BioMed Res. Int., 2014, 2014, 689219.
[PMID: 25045691]
Kulkarni-Kale, U; Bhosle, S; Kolaskar, AS A conformational epitope prediction server. Nucleic Acids Res, 2005, 33(Web Server issue), W168- W 171.
Kolaskar, A.S.; Kulkarni-Kale, U. Prediction of three-dimensional structure and mapping of conformational epitopes of envelope glycoprotein of Japanese encephalitis virus. Virology, 1999, 261(1), 31-42.
[] [PMID: 10441554]
Haste Andersen, P.; Nielsen, M.; Lund, O. Prediction of residues in discontinuous B-cell epitopes using protein 3D structures. Protein Sci., 2006, 15(11), 2558-2567.
[] [PMID: 17001032]
Sweredoski, M.J.; Baldi, P. PEPITO: Improved discontinuous B-cell epitope prediction using multiple distance thresholds and half sphere exposure. Bioinformatics, 2008, 24(12), 1459-1460.
[] [PMID: 18443018]
Moreau, V.; Fleury, C.; Piquer, D.; Nguyen, C.; Novali, N.; Villard, S.; Laune, D.; Granier, C.; Molina, F. PEPOP: computational design of immunogenic peptides. BMC Bioinformatics, 2008, 9, 71.
[] [PMID: 18234071]
Qi, T; Qiu, T; Zhang, Q; Tang, K; Fan, Y; Qiu, J; Wu, D; Zhang, W; Chen, Y; Gao, J SEPPA 2.0-more refined server to predict spatial epitope considering species of immune host and subcellular localiza- tion of protein antigen. Nucleic. Acids Res, 2014, 42(Web Server issue), W59-63.
Sun, J.; Wu, D.; Xu, T.; Wang, X.; Xu, X.; Tao, L.; Li, Y.X.; Cao, Z.W. A computational server for spatial epitope prediction of protein antigens. Nucleic Acids Res, 2009, 37(Web Server issue), W612-616.
Rubinstein, N.D.; Mayrose, I.; Martz, E.; Pupko, T. Epitopia: a web-server for predicting B-cell epitopes. BMC Bioinformatics, 2009, 10, 287.
[] [PMID: 19751513]
Liang, S.; Zheng, D.; Zhang, C.; Zacharias, M. Prediction of antigenic epitopes on protein surfaces by consensus scoring. BMC Bioinformatics, 2009, 10, 302.
[] [PMID: 19772615]
Liang, S.; Zheng, D.; Standley, D.M.; Yao, B.; Zacharias, M.; Zhang, C. EPSVR and EPMeta: prediction of antigenic epitopes using support vector regression and multiple server results. BMC Bioinformatics, 2010, 11, 381.
[] [PMID: 20637083]
Zhang, W.; Xiong, Y.; Zhao, M.; Zou, H.; Ye, X.; Liu, J. Prediction of conformational B-cell epitopes from 3D structures by random forests with a distance-based feature. BMC Bioinformatics, 2011, 12, 341.
[] [PMID: 21846404]
Zhao, L.; Hoi, S.C.; Li, Z.; Wong, L.; Nguyen, H.; Li, J. Coupling graphs, efficient algorithms and b-cell epitope prediction. IEEE/ACM Trans. Comput. Biol. Bioinformatics, 2014, 11(1), 7-16.
[] [PMID: 26355502]
Hu, Y.J.; Lin, S.C.; Lin, Y.L.; Lin, K.H.; You, S.N. A meta-learning approach for B-cell conformational epitope prediction. BMC Bioinformatics, 2014, 15, 378.
[] [PMID: 25403375]
Yao, B.; Zheng, D.; Liang, S.; Zhang, C. Conformational B-cell epitope prediction on antigen protein structures: A review of current algorithms and comparison with common binding site prediction methods. PLoS One, 2013, 8(4), e62249.
[ 10.1371/journal.pone.0062249] [PMID: 23620816]
Geysen, H.M.; Rodda, S.J.; Mason, T.J. A priori delineation of a peptide which mimics a discontinuous antigenic determinant. Mol. Immunol., 1986, 23(7), 709-715.
[] [PMID: 2432410]
Moreau, V.; Granier, C.; Villard, S.; Laune, D.; Molina, F. Discontinuous epitope prediction based on mimotope analysis. Bioinformatics, 2006, 22(9), 1088-1095.
[] [PMID: 16434442]
Mumey, B.; Angel, N.O.T. Filtering epitope alignments to improve protein surface prediction. ISPA., 2006.In: ISPA; Springer, 2006, pp. 648-657.
Mumey, B.M.; Bailey, B.W.; Kirkpatrick, B.; Jesaitis, A.J.; Angel, T.; Dratz, E.A. A new method for mapping discontinuous antibody epitopes to reveal structural features of proteins. J. Comput. Biol., 2003, 10(3-4), 555-567.
[] [PMID: 12935344]
Enshell-Seijffers, D.; Denisov, D.; Groisman, B.; Smelyanski, L.; Meyuhas, R.; Gross, G.; Denisova, G.; Gershoni, J.M. The mapping and reconstitution of a conformational discontinuous B-cell epitope of HIV-1. J. Mol. Biol., 2003, 334(1), 87-101.
[] [PMID: 14596802]
Bublil, E.M.; Freund, N.T.; Mayrose, I.; Penn, O.; Roitburd-Berman, A.; Rubinstein, N.D.; Pupko, T.; Gershoni, J.M. Stepwise prediction of conformational discontinuous B-cell epitopes using the Mapitope algorithm. Proteins, 2007, 68(1), 294-304.
[] [PMID: 17427229]
Halperin, I.; Wolfson, H.; Nussinov, R. SiteLight: binding-site prediction using phage display libraries. Protein Sci., 2003, 12(7), 1344-1359.
[] [PMID: 12824481]
Schreiber, A.; Humbert, M.; Benz, A.; Dietrich, U. 3D-Epitope-Explorer (3DEX): localization of conformational epitopes within three-dimensional structures of proteins. J. Comput. Chem., 2005, 26(9), 879-887.
[] [PMID: 15834923]
Mayrose, I.; Shlomi, T.; Rubinstein, N.D.; Gershoni, J.M.; Ruppin, E.; Sharan, R.; Pupko, T. Epitope mapping using combinatorial phage-display libraries: a graph-based algorithm. Nucleic Acids Res., 2007, 35(1), 69-78.
[] [PMID: 17151070]
Huang, J.; Gutteridge, A.; Honda, W.; Kanehisa, M. MIMOX: a web tool for phage display based epitope mapping. BMC Bioinformatics, 2006, 7, 451.
[] [PMID: 17038191]
Castrignanò, T.; De Meo, P.D.; Carrabino, D.; Orsini, M.; Floris, M.; Tramontano, A. The MEPS server for identifying protein conformational epitopes. BMC Bioinformatics, 2007, 8(Suppl. 1), S6.
[] [PMID: 17430573]
Mayrose, I.; Penn, O.; Erez, E.; Rubinstein, N.D.; Shlomi, T.; Freund, N.T.; Bublil, E.M.; Ruppin, E.; Sharan, R.; Gershoni, J.M.; Martz, E.; Pupko, T. Pepitope: Epitope mapping from affinity-selected peptides. Bioinformatics, 2007, 23(23), 3244-3246.
[] [PMID: 17977889]
Negi, S.S.; Braun, W. Automated detection of conformational epitopes using phage display Peptide sequences. Bioinform. Biol. Insights, 2009, 3, 71-81.
[] [PMID: 20140073]
Huang, Y.X.; Bao, Y.L.; Guo, S.Y.; Wang, Y.; Zhou, C.G.; Li, Y.X. Pep-3D-Search: a method for B-cell epitope prediction based on mimotope analysis. BMC Bioinformatics, 2008, 9, 538.
[] [PMID: 19087303]
Chen, W.H.; Sun, P.P.; Lu, Y.; Guo, W.W.; Huang, Y.X.; Ma, Z.Q. MimoPro: A more efficient Web-based tool for epitope prediction using phage display libraries. BMC Bioinformatics, 2011, 12, 199.
[] [PMID: 21609501]
Chen, W.; Guo, W.W.; Huang, Y.; Ma, Z. PepMapper: A collaborative web tool for mapping epitopes from affinity-selected peptides. PLoS One, 2012, 7(5), e37869.
[] [PMID: 22701536]
Sun, P.; Ju, H.; Zhang, B.; Gu, Y.; Liu, B.; Huang, Y.; Zhang, H.; Li, Y. Conformational B-cell epitope prediction method based on antigen preprocessing and mimotopes analysis. BioMed Res. Int., 2015, 2015, 257030.
[PMID: 25705652]
Sun, P.; Qi, J.; Zhao, Y.; Huang, Y.; Yang, G.; Ma, Z.; Li, Y. A novel conformational B-cell epitope prediction method based on mimotope and patch analysis. J. Theor. Biol., 2016, 394, 102-108.
[] [PMID: 26804644]
Sun, P.; Chen, W.; Huang, Y.; Wang, H.; Ma, Z.; Lv, Y. Epitope prediction based on random peptide library screening: benchmark dataset and prediction tools evaluation. Molecules, 2011, 16(6), 4971-4993.
[] [PMID: 21681149]
Zhang, C.; Li, Y.; Tang, W.; Zhou, Z.; Sun, P.; Ma, Z. The Relationship between B-cell epitope and mimotope sequences. Protein Pept. Lett., 2016, 23(2), 132-141.
[] [PMID: 26715528]
Rapberger, R.; Lukas, A.; Mayer, B. Identification of discontinuous antigenic determinants on proteins based on shape complementarities. J. Mol. Recognit., 2007, 20(2), 113-121.
[] [PMID: 17421048]
Soga, S.; Kuroda, D.; Shirai, H.; Kobori, M.; Hirayama, N. Use of amino acid composition to predict epitope residues of individual antibodies. Protein Eng. Des. Sel., 2010, 23(6), 441-448.
[] [PMID: 20304974]
Krawczyk, K.; Liu, X.; Baker, T.; Shi, J.; Deane, C.M. Improving B-cell epitope prediction and its application to global antibody-antigen docking. Bioinformatics, 2014, 30(16), 2288-2294.
[] [PMID: 24753488]
Ma, C.Z.B.S.W.T.P.S.Z. Prediction of conformational B-cell epitope binding with individual antibodies using phage display peptides. Int. J. Clin. Exp. Med., 2016, 9(2), 10.
Yiqi, L. Min, X.; Li, L.; Yu, H.; Ge, S.; Zhang, J.; Xia, N. Using a machine-learning approach to predict discontinuous antibody-specific b-cell epitopes. Curr. Bioinform., 2017, 9(12), 5.
Ashkenazy, H; Erez, E; Martz, E; Pupko, T ConSurf 2010: Calculating evolutionary conservation in sequence and structure of proteins and nucleic acids. Nucleic Acids Res, 2010, 38(Web Server issue), W529-W533.
Neuvirth, H.; Raz, R.; Schreiber, G. ProMate: A structure based prediction program to identify the location of protein-protein binding sites. J. Mol. Biol., 2004, 338(1), 181-199.
[] [PMID: 15050833]
Liang, S.; Zhang, C.; Liu, S.; Zhou, Y. Protein binding site prediction using an empirical scoring function. Nucleic Acids Res., 2006, 34(13), 3698-3707.
[] [PMID: 16893954]
Kufareva, I.; Budagyan, L.; Raush, E.; Totrov, M.; Abagyan, R. PIER: Protein interface recognition for structural proteomics. Proteins, 2007, 67(2), 400-417.
[] [PMID: 17299750]

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Year: 2019
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DOI: 10.2174/1568026619666181130111827
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