Dönnes Pierre, Kohlbacher Oliver
Department for Simulation of Biological Systems, WSI/ZBIT, Eberhard Karls University Tübingen, D-72076 Tübingen, Germany.
Protein Sci. 2005 Aug;14(8):2132-40. doi: 10.1110/ps.051352405. Epub 2005 Jun 29.
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-A0201, HLA-B2705, HLA-A01, and HLA-A03 alleles using WAPP. The method is available online through our prediction server at http://www-bs.informatik.uni-tuebingen.de/WAPP
表位驱动疫苗的合理设计是免疫信息学的一个关键目标。通常，候选物的选择仅依赖于MHC-肽结合的预测，因为已知这是MHC I类抗原加工途径中最具选择性的步骤。然而，蛋白酶体切割以及与抗原加工相关的转运体（TAP）介导的转运也是抗原加工的关键步骤。虽然针对各个步骤都存在预测方法，但尚无方法能够对所有三个主要加工事件进行综合预测。在此，我们介绍WAPP，一种将蛋白酶体切割、TAP转运和MHC结合预测整合到单一预测系统中的方法。蛋白酶体切割位点预测采用了一种基于实验验证的蛋白酶体切割位点的新型矩阵法。支持向量回归用于预测TAP转运的肽段。MHC结合是抗原加工途径的最后一步，采用支持向量机方法SVMHC进行预测。各个方法以模仿自然加工途径的过滤方式相结合。因此，WAPP预测在C末端被蛋白酶体切割、由TAP转运并与MHC I类分子具有显著亲和力的肽段。与仅进行MHC结合预测相比，这降低了假阳性率。与仅预测MHC结合相比，我们报告称使用WAPP对HLA-A0201、HLA-B2705、HLA-A01和HLA-A03等位基因的总体准确率提高，假阳性预测率降低。该方法可通过我们的预测服务器在线获取，网址为http://www-bs.informatik.uni-tuebingen.de/WAPP
