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Binding Affinity Calculations of Gluten Peptides to HLA Risk Modifiers: DQ2.5 versus DQ7.5
Yi Song1, Sangyun Lee2, David Bell2,3
1College of Life Sciences, Department of Physics, and Institute of Quantitative Biology, Zhejiang University, Hangzhou 310058, China.
The Journal of Physical Chemistry. B
|July 7, 2022
Summary
This study introduces a new Free Energy Perturbation (FEP) method to accurately predict binding affinities between different Human Leukocyte Antigens (HLAs) and various antigens, crucial for understanding celiac disease (CeD) pathogenesis.
Area of Science:
- Computational chemistry
- Immunology
- Structural biology
Background:
- Free Energy Perturbation (FEP) accurately predicts antigen-HLA binding affinities.
- Comparing binding affinities of different antigens to different HLAs using FEP is challenging.
- Existing FEP schemes for absolute binding affinities have shown varied success.
Purpose of the Study:
- To propose and assess a unifying FEP scheme for comparing binding affinities of different antigens to different HLAs.
- To apply this method to Human Leukocyte Antigen (HLA)-antigen-T-cell receptor (TCR) systems relevant to celiac disease (CeD).
- To investigate binding affinity differences between HLA-DQ2.5 (CeD risk) and HLA-DQ7.5 (CeD protective) for gliadin epitopes.
Main Methods:
- Developed a unifying scheme using absolute binding affinity FEP calculations.
- Employed carefully designed thermodynamic cycles for calculations.
- Applied the technique to HLA-DQ2.5 and HLA-DQ7.5 systems with three gliadin-derived epitopes.
Main Results:
- Demonstrated that HLA-DQ2.5 has higher binding affinity for gliadin than HLA-DQ7.5.
- Showed enhanced binding affinity of HLA-DQ2.5 with a common TCR.
- Results align with HLA-DQ2.5's association with increased CeD risk.
Conclusions:
- The proposed absolute binding affinity FEP method is suitable for predicting HLA binding for disparate antigens and genotypes.
- The study provides atomic-level insights into HLA-gluten peptide-TCR interactions in CeD pathogenesis.
