Peptide binding to HLA-DP proteins at pH 5.0 and pH 7.0: a quantitative molecular docking study

The X-ray structure of the peptide – HLA-DP2 protein complex was used as a starting template to model by homology the structure of the four DP proteins. The resulting models were used to produce virtual combinatorial peptide libraries constructed using the single amino acid substitution (SAAS) principle. Peptides were docked into the DP binding site using AutoDock at pH 5.0 and pH 7.0. The resulting scores were normalized and used to generate Docking Score-based Quantitative Matrices (DS-QMs). The predictive ability of these QMs was tested using an external test set of 484 known DP binders. They were also compared to existing servers for DP binding prediction. The models derived at pH 5.0 predict better than those derived at pH 7.0 and showed significantly improved predictions for three of the four DP proteins, when compared to the existing servers. They are able to recognize 50% of the known binders in the top 5% of predicted peptides.The higher predictive ability of DS-QMs derived at pH 5.0 may be rationalised by the additional hydrogen bond formed between the backbone carbonyl oxygen belonging to the peptide position before p1 (p-1) and the protonated ε-nitrogen of His79β. Additionally, protonated His residues are well accepted at most of the peptide binding core positions which is in a good agreement with the overall negatively charged peptide binding site of most MHC proteins.Major histocompatibility complex class II (MHC class II) proteins are normally found in B lymphocytes, dendritic cells, and macrophages; they are primarily involved in processing foreign, extracellular antigens, which are endocytozed and then enclosed in endosomes containing acid proteases. The pH in endosomes ranges from 4.5 to 6.0 [1]. In endosomes, antigens are degraded into oligopeptides. MHC class II proteins are synthesized in the endoplasmic reticulum (ER) and bind to a protein known as the MHC class II-associated invariant chain (Ii). Ii facilitates the export from the ER of MHC cl