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Prediction of B cell epitopes

Prediction of B cell epitopes. Pernille Haste Andersen Immunological Bioinformatics CBS, DTU pan@cbs.dtu.dk. B cells and antibodies. Antibodies are produced by B lymphocytes (B cells) Antibodies circulate in the blood They are referred to as “the first line of defense” against infection

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Prediction of B cell epitopes

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  1. Prediction of B cell epitopes Pernille Haste Andersen Immunological Bioinformatics CBS, DTU pan@cbs.dtu.dk

  2. B cells and antibodies • Antibodies are produced by B lymphocytes (B cells) • Antibodies circulate in the blood • They are referred to as “the first line of defense” against infection • Antibodies play a central role in immunity by attaching to pathogens and recruiting effector systems that kill the invader

  3. What is a B cell epitope? B cell epitopes • Accessible and recognizable structural feature of a pathogen molecule (antigen) • Antibodies are developed to bind the epitope with high affinity by using the complementarity determining regions (CDRs) Antibody Fab fragment B cell epitope

  4. Motivations for prediction of B cell epitopes • Prediction of B cell epitopes can potentially guide experimental epitope mapping • Predictions of antigenicity in proteins can be used for selecting subunits in rational vaccine design • Predictions of B cell epitopes may also be valuable for interpretation of results from experiments based on antibody affinity binding such as ELISA, RIA and western blotting

  5. Computational Rational Vaccine Design >PATHOGEN PROTEIN KVFGRCELAAAMKRHGLDNYRGYSLGNWVCAAKFESNF Rational Vaccine Design

  6. B cell epitopes, linear or discontinuous? • Classified into linear (~10%) and discontinuous epitopes (~90%) • Databases: AntiJen, IEDB, BciPep, Los Alamos HIV database, Protein Data Bank • Large amount of data available for linear epitopes • Few data available for discontinuous epitopes • In general, B cell epitope prediction methods have relatively low performances

  7. Discontinuous B cell epitopes • SLDEKNSVSVDLPGEMKVLVSKEKNKDGKYDLIATVDKLELKGTSDKNNGSGVLEGVKADKCKVKLTISDDLGQTTLEVFKEDGKTLVSKKVTSKDKSSTEEKFNEKGEVSEKIITRADGTRLEYTGIKSDGSGKAKEVLKG • ..\Discotope\1OSP_epitope\1OSP_epitope.psw An example: The epitope of the outer surface protein A from Borrelia Burgdorferi (1OSP)

  8. A data set of 3D discontinuous epitopes • A data set of 75 discontinuous epitopes was compiled from structures of antibodies/protein antigen complexes in the PDB • The data set has been used for developing a method for predictions of discontinuous B cell epitopes • Since about 30 of the PDB entries represented Lysozyme, I have used homology grouping (25 groups of non-homologous antigens) and 5 fold cross-validation for training of the method • Performance was measured using ROC curves on a per antigen basis, and by weighted averaging of AUC values

  9. Epitope log-odds ratios • Frequencies of amino acids in epitopes compared to frequencies of non-epitopes • Several discrepancies compared to the Parker hydrophilicity scale which is often used for epitope prediction • Both methods are used for predictions using a sequential average of scores • Predictive performance of B cell epitopes: • Parker 0.614 AUC • Epitope log–odds 0.634 AUC

  10. 3D information: Contact numbers • Surface exposure and • structural protrusion can • be measured by residue • contact numbers • The predictive performance: • Parker 0.614 AUC • Epitope log–odds 0.634 AUC • Contact numbers 0.647 AUC

  11. DiscoTope : Prediction of Discontinuous epiTopes using 3D structures • A combination of: • Sequentially averaged epitope log-odds values of residues in spatial proximity • Contact numbers .LIST..FVDEKRPGSDIVED……ALILKDENKTTVI. -0.145 +0.691+0.346+1.136+1.180+1.164 +1.136 +0.346 Sum of log-odds values Contact number : K 10 DiscoTope prediction value

  12. DiscoTope : Prediction of Discontinuous epiTopes • Improved prediction of residues in discontinuous B cell epitopes in the data set • The predictive performance on B cell epitopes: Parker 0.614 AUC Epitope log–odds 0.634 AUC Contact numbers 0.647 AUC DiscoTope 0.711 AUC

  13. Evaluation example AMA1 • Apical membrane antigen 1 from Plasmodium falciparum (not used for training/testing) • Two epitopes were identified using phage-display, point-mutation (black side chains) and sequence variance analysis (side chains of polyvalent residues in yellow) • Most residues identified as epitopes were successfully predicted by DiscoTope (green backbone) ..\Discotope\1Z40_epitope\1Z40_movie.mov DiscoTope is available as web server: http://www.cbs.dtu.dk/services/DiscoTope/

  14. Future improvements • Add epitope predictions for protein-protein complexes • Visualization of epitopes integrated in web server • Testing a score for sequence variability fx based on entropy of positions in the antigens • Combination with glycosylation site predictions • Combination with predictions of trans-membrane regions • Assembling predicted residues into whole epitopes

  15. Presentation of the web server

  16. Presentation of the web server output

  17. Acknowledgements • DiscoTope • Ole Lund • Ideas, supervision and support • Morten Nielsen • Ideas, development of method and web server • Nicholas Gauthier • Improving the method, improving the web server

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