Prediction of B cell epitopes
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Prediction of B cell epitopes
Pernille Haste Andersen
Immunological Bioinformatics
CBS, DTU
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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
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What is a B cell epitope?
Antibody Fabfragment
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)
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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
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Computational Rational Vaccine Design
>PATHOGEN PROTEINKVFGRCELAAAMKRHGLDNYRGYSLGNWVCAAKFESNF
Rational Vaccine Design
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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
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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)
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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
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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 AUCEpitope log–odds 0.634 AUC
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3D information: Contact numbers
Surface exposure andstructural protrusion canbe measured by residuecontact numbers
The predictive performance:
Parker 0.614 AUCEpitope log–odds 0.634 AUCContact numbers 0.647 AUC
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DiscoTope : Prediction of Discontinuous epiTopes using 3D structures
A combination of:– Sequentially averaged epitope log-
odds values of residues in spatial proximity
– Contact numbers
-0.145
+0.346+1.136
+0.691+0.346+1.136+1.180+1.164
Contact number : K 10
DiscoTope prediction value
Sum of log-odds values
.LIST..FVDEKRPGSDIVED……ALILKDENKTTVI.
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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
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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 is available as web server: http://www.cbs.dtu.dk/services/DiscoTope/
..\Discotope\1Z40_epitope\1Z40_movie.mov
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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
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Presentation of the web server
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Presentation of the web server output
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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