Modelling of HLA-DQ2 and its interaction with gluten peptides to explain molecular recognition in celiac disease

Celiac disease (CD) is sustained by abnormal intestinal mucosal T-cell response to gluten and it is strongly associated with HLA class II molecules encoded by DQA1*0501/DQB1*02 (DQ2) or DQA1*03/DQB1*0302 (DQ8). The in vitro stimulatory activity of gliadin increases after treatment with tissue transglutaminase (tTG) which catalyses the deamidation of specific residues of glutamine to glutamate that can serve as anchors for binding to DQ2 as well as to DQ8 molecules. We modelled the three-dimensional structure of the DQ2 dimer protein, the most frequent in celiac patients, by using a homology modelling strategy, and deposited the model in the Protein Data Bank (PDB). Then, we simulated the interactions of DQ2 with different gluten peptides and the deamidation of specific peptide glutamines in the known p4, p6, p7 and p9 anchor positions, as well as in p1 and p5 positions, and other substitutions for which experimental effects on binding are available by previous experimental studies. By evaluating the energy of interaction and the H-bond interactions, we were able to distinguish what substitutions improve the interaction peptide-DQ2, in agreement with previously published experimental data. By analysing the peptide-DQ2 complex at the atom level, we observed that these glutamate side chains can interact with specific positively charged amino acids of DQ2, absent in other HLA alleles not related to celiac disease. The simulation was also extended to other peptides, related to celiac disease but for which no experimental data exists about the effects of glutamine deamidation. Our results give an interpretation at the molecular level of previously reported binding experimental data and open a new window to gain further insights about peptide recognition in celiac disease.