Protein epitope prediction and analysisePitope InformaticsePitope Informatics








This page provides a selection of historical references concerning epitope prediction and related protein analysis and annotation.

A substantial revision providing up-to-date references is planned.


ePitope Informatics listings in Nature feature articles:

Protein antigenicity prediction algorithms

Hopp and Woods
Hopp, T.P. and Woods, K.R. (1981). Prediction of protein antigenic determinants from amino acid sequences. Proceedings of the National Academy of Sciences USA, 78: 3824-3828.

Parker, J.M.R., Guo, D. and Hodges, R.S. (1986). New hydrophilicity scale derived from high-performance liquid chromatography retention data: correlation of predicted surface residues with antigenicity and X-ray derived accessible sites. Biochemistry, 25, 5425.

Protrusion Index (Thornton)
Thornton, J.M, Edwards, M.S., Tayler, W.R. and Barlow, D.J. (1986). Location of 'continuous' antigenic determinants in the protruding regions of proteins. EMBO Journal, 5: 409-413.

Protein hydrophobicity algorithms

Fauchere, J.L. and Pliska, V. (1983). Hydrophobic parameters p of amino-acid side chains from the partitioning of N-acetyl-amino-acid amides  European Journal of Medicinal Chemistry (Chim. Ther.), 18: 369-375.

Janin, J. (1979). Surface and inside volumes in globular proteins. Nature (London), 277: 491-492.

Kyte and Doolittle
Kyte, J. and Doolittle, R.F.(1982). A simple method for displaying the hydropathic character of a protein. Journal of Molecular Biology, 157: 105-132.

Manavalan, P. and Ponnuswamy, P.K. (1978). Hydrophobic character of amino acid residues in globular proteins. Nature (London), 275: 673-674.

Sweet and Eisenberg
Sweet, R.M. and Eisenberg, D. (1983). Correlation of sequence hydrophobicities measures similarity in three-dimensional protein structure. Journal of Molecular Biology, 171: 479-488.

Protein hydrophilicity algorithms

Goldman, Engelman and Steitz (GES)
Engelman, D.M., Steitz, T.A. and Goldman, A. (1986). Identifying nonpolar transmembrane helices in amino acid sequences of membrane proteins. Annual Review of Biophysics and Biophysical Chemistry, 15: 321-353.

von Heijne
von Heijne, G. (1981). On the hydrophobic nature of signal sequences. European Journal of Biochemistry, 116: 419-422.

Protein flexibility prediction algorithm

Karplus and Schulz
Karplus, P.A. and Schulz, G.E. (1985). Prediction of chain flexibility in proteins: a tool for the selection of peptide antigens. Naturwissenschaften, 72: 212-213.

Protein secondary structure prediction algorithms

GOR II & IV methods (Garnier and Robson)
Garnier, J. and Robson, B. (1989). The GOR method for predicting secondary structures in proteins. In Prediction of Protein Structure and the Principles of Protein Conformation (ed. G.D. Fasman), Vol. 11, pp. 417-465. Plenum Press, New York.

Garnier, J., Osguthorpe, D.J. and Robson, B. (1978). Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. Journal of Molecular Biology, 120: 97-120.

Garnier, J., Gibrat, J-F. and Robson, B., Methods Enzymol., 266: 540-553, 1996.

Chou and Fasman
Chou, P.Y. and Fasman, G.D. (1974). Conformational parameters for amino acids in helical, ß-sheet, and random coil regions calculated from proteins. Biochemistry, 13: 211-222.

Lewis, P.N., Momany, F.A. and Scheraga, H. A. (1971). Folding of polypeptide chains in proteins: a proposed mechanism for folding. Proceedings of the National Academy of Sciences USA, 68: 2293-2297.

Chou, P.Y. and Fasman, G.D. (1978). Empirical predictions of protein conformation. Annual Review of Biochemistry, 47: 251-276.

Chou, P.Y. and Fasman, G.D. (1978). Prediction of the secondary structure of proteins from their amino acid sequence. Advances in Enzymology, 47: 45-148.

B cell epitope prediction reviews

Van Regenmortel, M.H.V. (1996). Mapping epitope structure and activity: from one-dimensional prediction to four-dimensional description of antigenic specificity. Methods: a companion to Methods in Enzymology, 9: 465-472.

Pellequer, J-L., Westhof, E. and Van Regenmortel, M.H.V. (1994). Epitope predictions from the primary structure of proteins. In Peptide antigens: a practical approach (ed. G.B. Wisdom), pp. 7-25. Oxford University Press, Oxford.

Carter, J.M. (1994). Epitope prediction methods. In Methods in Molecular Biology (ed. B.M. Dunn and M.W. Pennington), Vol. 36, pp. 193-206. Human Press Inc., New Jersey.

Van Regenmortel, M.H.V. (1992). Molecular dissection of protein antigens. In Structure of antigens (ed. M.H.V. Van Regenmortel), Vol. 1, pp. 1-27. CRC Press, Boca Raton.

Stern, P.S. (1991). Predicting antigenic sites on proteins. Trends in Biotechnology, 9: 163-169.

Pellequer, J.L., Westhof, E. and Van Regenmortel, M.H.V. (1991). Predicting location of continuous epitopes in proteins from their primary structures. Methods in Enzymology, 203: 176-201.

Laver, W.G., Air, G.M., Webster, R.G. and Smith-Gill, S.J. (1990). Epitopes on protein antigens: misconceptions and realities. Cell, 61: 553-556.

Hopp, T.P. (1989). Use of hydrophilicity plotting procedures to identify protein antigenic segments and other interaction sites. Methods in Enzymology, 178: 571-585.

Van Regenmortel, M.H.V. (1989). The concept and operational definition of protein epitopes. Philosophical Transactions of the Royal Society of London, 323: 451-466.

Getzoff, E.D., Tainer, J.A., Lerner, R.A. and Geysen, H.M. (1988). The chemistry and mechanism of antibody binding to protein antigens. Advances in Immunology, 43: 1-98.

Van Regenmortel, M.H.V. and de Marcillac, G.D. (1988). An assessment of prediction methods for locating continuous epitopes in proteins. Immunology Letters, 17: 95-108.

Hopp, T.P. (1986). Protein surface analysis: methods for identifying antigenic determinants and other interaction sites. Journal of Immunological Methods, 88: 1-18.

Van Regenmortel, M.H.V. (1986). Which structural features determine protein antigenicity? Trends in Biochemical Sciences, 11: 36-39.

Other B cell epitope prediction

Alix, A.J.P. (2000). Predictive estimation of protein linear epitopes by using the program PEOPLE. Vaccine, 18: 311-314.

B cell epitopes. Some application data. Program's accuracy not reported.

Vihinen, M., Torkkila, E. and Riikonen, P. (1994). Accuracy of protein flexibility predictions. Proteins: structure, function, and genetics, 19: 141-149.

Maksyutov, A.Z. and Zagrebelnaya, E.S. (1993). ADEPT: a computer program for prediction of protein antigenic determinants. Bioinformatics, 9: 291-297.

B and T cell epitopes. No validation data. Program's accuracy not reported.

Hofmann, H-J., Hädge, D., Höltje, M. and Höltje, H-D. (1991). Theoretical prediction of antigenic determinants based on protein-water interaction energies. Quantitative Structure-Activity Relationships, 10: 300-305.

Hofmann, H-J., Hädge, D., Höltje, M. and Höltje, H-D. (1990). Protein-water interaction energies as predictor for antigenic determinants. Molecular Immunology, 27: 1057-1060.

Krchñák, V., Mach, O. and Malý, A. (1989). Computer prediction of B-cell determinants from protein amino acid sequences based on incidence of b turns. Methods in Enzymology, 178: 586-611.

Stern, P.S. (1989). Normal-mode dynamics as a tool for predicting antigenic sites on proteins. Progress in Clinical Biological Research, 289: 87-94.

Jameson, B.A. and Wolf, H. (1988). The antigenic index: a novel algorithm for predicting antigenic determinants. Bioinformatics, 4: 181-186.

Cornette, J.L., Cease, K.B., Margalit, H., Spouge, J.L., Berzofsky, J.A. and DeLisi, C. (1987). Hydrophobicity scales and computational techniques for detecting amphipathic structures in proteins. Journal of Molecular Biology, 195: 659-685


Sequence Database Searches - BLAST

Altschul, S.F., Warren, G., Miller, W., Myers, E.W. and Lipman, D.J. (1990). Basic local alignment search tool. Journal of Molecular Biology, 215: 403-410.

Gish, W. and States, D.J. (1993). Identification of protein coding regions by database similarity search. Nature Genetics, 3:266-272.

Henikoff, S. and. Henikoff, J.G. (1992). Amino acid substitution matrices from protein blocks. Proceedings of the National Academy of Science USA, 89: 10915-10919.

Karlin, S. and Altschul, S.F. (1990). Methods for assessing the statistical significance of molecular sequence features by using general scoring schemes. Proceedings of the National Academy of Sciences USA, 87: 2264-2268.

Karlin, S. and Altschul, S.F. (1993). Applications and statistics for multiple high-scoring segments in molecular sequences. Proceedings of the National Academy of Sciences USA, 90: 5873-5877.

Sequence Retrieval Searches - Entrez

Benson, D.A., Boguski, M.S., Lipman, D.J., Ostell, J., Ouellette, B.F.F., Rapp, B.A., Wheeler, D.L. (1999). GenBank. Nucleic Acids Research, 27: 12-17.

McEntyre, J (1998). Linking up with Entrez. Trends in Genetics, 14: 39-40.

Schuler, G.D., Epstein, J.A., Ohkawa, H. and Kans, J.A. (1996). Entrez: molecular biology database and retrieval system. Methods in Enzymology, 266: 141-162.

Sequence Database Searches - PROSITE

Bairoch, A., Bucher, P. and Hofmann, K. (1997). The PROSITE database, its status in 1997. Nucleic Acids Research, 25: 217-221.

Other Bioinformatics

Attwood, T.K. and Parry-Smith, D.J. (2001). Introduction to bioinformatics. Prentice Hall, New Jersey.

A very good general introductory text. Especially relevant, are the sections detailing protein information resources and sequence searching.

Bioinformatics: genes, proteins and computers. Eds Orengo, C.A., Jones, D.T. and Thornton, J.M., BIOS Scientific Publishers Ltd, Oxford, 2003.

Another very good general introductory-to-advanced text, with a strong focus in areas including protein structure and function, and proteomics.

Peri, S., Ibarrola, N., Mann, M. and Pandey, A. (2001). Common pitfalls in bioinformatics-based analyses: look before you leap. Trends in Genetics, 17: 541-545.

Pruitt, K.D. and Maglott, D.R. (2001). RefSeq and LocusLink: NCBI gene-centered resources. Nucleic Acids Research, 29: 137-140.

Protein structure

Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N. and Bourne, P.E. (2000). The Protein Data Bank, Nucleic Acids Research, 28: 235-242.

Branden, C. and Tooze, J. (1991) Introduction to Protein Structure. Garland, New York.

Hogue, C.W.V. (1997). Cn3D: a new generation of three-dimensional molecular structure viewer, Trends in Biochemical Sciences, 22: 314-316.

Stanfield, R. L. and Wilson, I.A. (1993) X-Ray Crystallographic Studies of Antibody-Peptide Complexes. Immunomethods, 3: 211-221.

Sayle, R. and Milner-White, E. J. (1995). RasMol: Biomolecular graphics for all. Trends in Biochemical Sciences, 20: 374.

Wibley, J. E. A., Pegg, A. E., Moody, P. C. E. (2000). Crystal structure of human O6-alkylguanine-DNA alkyltransferase. Nucleic Acids Research, 28: 393-401.

Reference reporting the structure of the rotating molecule (MGMT) on our home page (PDB #: 1QNT).

Wilson, I.A. and Stanfield, R. L. (1994) Antibody-Antigen Interactions: New Structure and New Conformational Changes. Current Opinion in Structural Biology, 4: 857-867.

Immunochemistry and Molecular Immunology

Brusic, V., Zeleznikow, J. and Petrovsky, N. (2000). Molecular immunology databases and data repositories. Journal of Immunological Methods, 238: 17-28 [review].

Harlow, E. and Lane, D. (1999). Using antibodies: a laboratory manual. Cold Spring Harbor Laboatory Press, Cold Spring Harbor, New York.

A very good general reference text. Especially relevant, are the sections describing the choice and uses of antibodies, epitope structure, immunochemical detection of linear and conformational epitopes, and chemical modification and steric blocking of epitopes.

New technologies utilising antibodies for proteomics studies and diagnostics

Blagoev, B. and Pandey, A. (2001). Microarrays go live - new prospects for proteomics. Trends in Biochemical Sciences, 26: 639-641.

Liotta, L. and Petricoin, E. (2000). Molecular profiling of human cancer. Nature Reviews - Genetics 1: 48-56.

Borrebaeck, C.A.K. (2000). Antibodies in diagnostics - from immunoassays to protein chips. Immunology Today 21: 379-382. (Review)

T cell epitopes and prediction

Guan, P., Doytchinova, I.A., Zygouri, C. and Flower, D.R. (2003). MHCPred: bringing a quantitative dimension to the online prediction of MHC binding. Applied Bioinformatics, 2: 63-66.

Blythe, M.J., Doytchinova, I.A. and Flower, D.R. (2002). JenPep: a database of quantitative functional peptide data for immunology. Bioinformatics, 18: 434-439.

Flower, D.R. and Doytchinova, I.A. (2002). Immunoinformatics and the prediction of immunogenicity. Applied Bioinformatics, 1: 167-176.

Yu, K., Petrovsky, N., Schonbach, C., Koh, J.Y. and Brusic, V. (2002). Methods for prediction of peptide binding to MHC molecules: a comparative study. Molecular Medicine, 8: 137-48.

Brusic, V., Petrovsky, N., Zhang, G. and Bajic, V. (2002). Prediction of promiscuous peptides that bind HLA class I molecules. Immunology and Cell Biology, 80: 280-285.

Jung, G., Fleckenstein, B., von der Mülbe, F., Wessels, J., Niethammer, D. and Wiesmüller, K-H. (2001). From combinatorial libraries to MHC ligand motifs, T-cell superagonists and antagonists. Biologicals, 29: 179-181.

(describes T cell epitope prediction programme EPIPREDICT)

Kwok, W.W., Gebe, J.A., Liu, A., Agar, S., Ptacek, N., Hammer, J., Koelle, D.M. and Nepom, G.T. (2001). Rapid epitope identification from complex class-II-restricted T-cell antigens. Trends in Immunology, 22: 583-588.

(comparison of the use of the TEPITOPE algorithm with epitope mapping using the MHC-tetramer-guided approach)

Mallios, R.R. (2001). Predicting class II MHC/peptide multilevel binding with an iterative stepwise discriminative analysis meta-algorithm. Bioinformatics, 17: 942-948.

Römisch, K. (2001). How antigenic peptides are made to fit their groove. Trends in Biochemical Sciences, 26: 531.

Schirle, M., Weinschenk, T. and Stevanovic, S. (2001). Combining computer algorithms with experimental approaches permits the rapid and accurate identification of T cell epitopes from defined antigens. Journal of Immunological Methods, 257: 1-16.

Singh, H. and Raghava, G.P.S. (2001) ProPred: prediction of HLA-DR binding sites. Bioinformatics, 17: 1236-1237.

Andersen, M.H., Tan, L., Søndergaard, I., Zeuthen, J., Elliott, T. and Haurum, J.S. (2000). Poor correspondence between predicted and experimental binding of peptides to class I MHC molecules. Tissue Antigens, 55: 519-531.

Buus, S. (1999). Description and prediction of peptide-MHC binding: the 'human MHC project'. Current Opinion in Immunology, 11: 209-213.

De Groot, A.S. and Rothman, F.G. (1999). In silico predictions; in vivo veritas. Nature Biotechnology, 17: 533-534.

Mallios, R.R. (1999). Class II quantitative binding motifs derived from a large molecular database with a versatile iterative stepwise discriminative analysis meta-algorithm. Bioinformatics, 15: 432-439.

Pinilla, C., Martin, R., Gran, B., Appel, J.R., Boggiano, C., Wilson, D.B. and Houghten, R.A. (1999). Exploring immunological specificity using synthetic peptide combinatorial libraries. Current Opinion in Immunology, 11: 193-202.

(T cell epitope identification using synthetic peptide libraries)

Rammensee, H., Bachmann, J., Emmerich, N.P., Bachor, O.A. and Stevanovic, S. (1999). SYFPEITHI: a database for MHC ligands and peptide motifs. Immunogenetics, 50: 213-219.

Sturniolo, T., Bono, E., Ding, J., Raddrizzani, L., Tuereci, O., Sahin, U., Braxenthaler, M., Gallazzi, F., Protti, M.P., Sinigaglia, F. and Hammer, J. (1999). Generation of tissue-specific and promiscuous HLA ligand databases using DNA microarrays and virtual HLA class II matrices. Nature Biotechnology, 17: 555-561.

Brusic, V., Rudy, G., Honeyman, G., Hammer, J. and Harrison, L. (1998). Prediction of MHC class II-binding peptides using an evolutionary algorithm and artificial neural network. Bioinformatics, 14: 121-130.

Honeyman, M.C., Brusic, V., Stone, N.L. and Harrison, L.C. (1998). Neural network-based prediction of candidate T-cell epitopes. Nature Biotechnology, 16: 966-969.

Maffei, A. and Harris, P.E. (1998). Peptides bound to major histocompatibility complex molecules. Peptides, 19: 179-198.

Hammer, J., Sturniolo, T. and Sinigaglia, F. (1997). HLA class II binding specificity and autoimmunity. Advances in Immunology, 66: 67-100.

Van den Eynde, B. and van der Bruggen, P. (1997). T cell defined tumour antigens. Current Opinion in Immunology, 9: 684-693.

Wilson, I.A. and Garcia, K.C. (1997). T-cell receptor structure and TCR complexes. Current Opinion in Structural Biology, 7: 839-848.

Walden, P. (1996). T-cell epitope determination. Current Opinion in Immunology, 8: 68-74.

Deavin, A.J., Auton, T.R. and Greaney, P.J. (1996). Statistical comparison of established T-cell epitope predictors against a large database of human and murine antigens. Molecular Immunology, 33: 145-155.

Saavedra, R., Beccerril, M.A., Dubeaux, C., Lippens, R., De Vos, M-J., Herion, P. and Bollen, A. (1996). Epitopes recognised by human T lymphocytes in the ROP2 protein antigen of Toxoplasma gondii. Infection and immunity, 64: 3858-3862.

(compares three algorithms for T cell epitope prediction)

Rammensee, H-G. (1995). Chemistry of peptides associated with MHC Class I and Class II molecules. Current Opinion in Immunology, 7: 85-96.

Hammer, J., Gallazzi, F. and Sinigaglia, F. (1995). Molecular understanding of MHC peptide binding specificity and prediction of T-cell epitopes. Periodicum Biologorum, 98: 155-158.

Davenport, M.P., Ho Shon, I.A.P. and Hill, A.V.S. (1995). An empirical method for the prediction of T-cell epitopes. Immunogenetics, 42: 392-397.

Meister, G.E., Roberts, C.G.P., Berzofsky, J.A. and De Groot, A.S. (1995). Two novel T cell epitope prediction algorithms based on MHC-binding motifs; comparison of predicted and published epitopes from Mycobacterium tuberculosis and HIV protein sequences. Vaccine, 13: 581-591.

Hammer, J. (1995). New methods to predict MHC-binding sequences within protein antigens. Current Opinion in Immunology, 7: 263-269.

Rötzschke, O. and Falk, K. (1994). Origin, structure and motifs of naturally processed MHC class II ligands. Current Opinion in Immunology, 6: 45-51.

Hammer, J., Bono, E.,  Gallazzi, F., Belunis, C., Nagy, Z. and Sinigaglia, F. (1994). Precise prediction of Major Histocompatibility Complex Class II-peptide interaction based on peptide side chain scanning. Journal of Experimental Medicine, 180: 2353-2358.

Sinigaglia, F. and Hammer, J. (1994). Defining rules for the peptide-MHC class II interaction. Current Opinion in Immunology, 6: 52-56.

Hobohm, U. and Meyerhans, A. (1993). A pattern search method for putative anchor residues in T cell epitopes. European Journal of Immunology, 23: 1271-1276.

Reyes, V.E., Lew, R.A., Lu, S. and Humphreys, R.E. (1991). Prediction of a helices and T cell-presented sequences in proteins with algorithms based on strip-of-helix hydrophobicity index. Methods in Enzymology, 202: 225-238.

Menédez-Arias, L. and Rodríguez, R. (1990). A BASIC microcomputer program for prediction of B and T cell epitopes in proteins. Bioinformatics, 6: 101-105.

(main focus of report is T cell epitope prediction)

Cornette, J.L., Margalit, H., DeLisi, C. and Berzofsky, J.A. (1989). Identification of T-cell epitopes and use in construction of synthetic vaccines. Methods in Enzymology, 178: 611-634.

Stille, C.J., Thomas, L.J., Reyes, V.E. and Humphreys, R.E. (1987). Hydrophobic strip-of-helix algorithm for selection of T cell-presented peptides. Molecular Immunology, 24: 1021-1027.



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