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

Area of Science:

• Immunology
• Structural Biology
• Computational Biology

Background:

• Human Leukocyte Antigen (HLA)-DP proteins are crucial for immune responses.
• Peptide binding to MHC class II proteins occurs in acidic endosomal environments.
• Histidine protonation at acidic pH influences peptide-MHC interactions.

Purpose of the Study:

• To develop a predictive method for peptide binding to four common HLA-DP proteins.
• To investigate the effect of pH on peptide-HLA-DP binding predictions.
• To create accurate Docking Score-based Quantitative Matrices (DS-QMs).

Main Methods:

• Homology modeling of HLA-DP proteins based on HLA-DP2 crystal structure.
• Generation of virtual combinatorial peptide libraries using the SAAS principle.
• Molecular docking simulations performed at pH 5.0 and pH 7.0 using AutoDock.

Main Results:

• DS-QMs were generated from docking scores at both pH values.
• DS-QMs derived at pH 5.0 demonstrated superior predictive performance.
• The pH 5.0 models significantly outperformed existing servers for three out of four DP proteins.
• The method identified 50% of known binders within the top 5% of predicted peptides.

Conclusions:

• The enhanced predictive power at pH 5.0 is attributed to a specific hydrogen bond involving protonated Histidine 79β.
• Protonated Histidine residues are favorably accommodated in the negatively charged peptide-binding site of MHC proteins.
• The findings support the importance of considering pH in peptide-MHC binding predictions.