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Integrated modeling of the major events in the MHC class I antigen processing pathway

Department for Simulation of Biological Systems, WSI/ZBIT, Eberhard Karls University Tübingen, D-72076 Tübingen, Germany

(RECEIVED January 12, 2005; FINAL REVISION May 17, 2005; ACCEPTED May 18, 2005)

Rational design of epitope-driven vaccines is a key goal of immunoinformatics. Typically, candidate selection relies on the prediction of MHC–peptide binding only, as this is known to be the most selective step in the MHC class I antigen processing pathway. However, proteasomal cleavage and transport by the transporter associated with antigen processing (TAP) are essential steps in antigen processing as well. While prediction methods exist for the individual steps, no method has yet offered an integrated prediction of all three major processing events. Here we present WAPP, a method combining prediction of proteasomal cleavage, TAP transport, and MHC binding into a single prediction system. The proteasomal cleavage site prediction employs a new matrix-based method that is based on experimentally verified proteasomal cleavage sites. Support vector regression is used for predicting peptides transported by TAP. MHC binding is the last step in the antigen processing pathway and was predicted using a support vector machine method, SVMHC. The individual methods are combined in a filtering approach mimicking the natural processing pathway. WAPP thus predicts peptides that are cleaved by the proteasome at the C terminus, transported by TAP, and show significant affinity to MHC class I molecules. This results in a decrease in false positive rates compared to MHC binding prediction alone. Compared to prediction of MHC binding only, we report an increased overall accuracy and a lower rate of false positive predictions for the HLA-A*0201, HLA-B*2705, HLA-A*01, and HLA-A*03 alleles using WAPP. The method is available online through our prediction server at http://www-bs.informatik.uni-tuebingen.de/WAPP.

Keywords: MHC class I antigen processing; integrated modeling; proteasomal cleavage; TAP transport; MHC binding

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051352405.

Reprint requests to: Pierre Dönnes, Department for Simulation of Biological Systems, WSI/ZBIT, Eberhard Karls University Tübingen, Sand 14, D-72076 Tübingen, Germany; e-mail: doennes{at}informatik.uni-tuebingen.de; fax: +49-7071-29-5152.

Supplemental material: see www.proteinscience.org

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