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Prediction of B cell epitopes
Pernille Haste Andersen
Immunological Bioinformatics
CBS, DTU
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
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)
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
Computational Rational Vaccine Design
>PATHOGEN PROTEINKVFGRCELAAAMKRHGLDNYRGYSLGNWVCAAKFESNF
Rational Vaccine Design
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
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)
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
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
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
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.
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
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
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
Presentation of the web server
Presentation of the web server output
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