Effect of gliadin modification on CXCR3 binding

Gluten, the protein of wheat, is a complex molecule made of gliadin and glutenins; it is considered as "the environmental component" triggering Celiac disease (CD) since its components are both toxic for CD patients. During digestion, gliadin is reduced into small peptides of about 20 amino acids enriched in glutamine and prolines. These peptides can be deamidated by transglutaminase, converting specific glutamine (Q) residues into glutamic acid (E). In the intestinal epithelium the isoforms A and B of CX-Chemokine Receptor Type 3 (CXCR3), a G-Protein Coupled Receptor, specifically binds two of the gliadin peptides (111-130 and 151-170). Both gliadin and CXCR3 involved in CD onset. Evaluate the differential binding of the two-gliadin peptides. Evaluate differences between deamidated peptides and normal while binding the two CXCR3 isoforms (A and B). HADDOCK run returned up to 14 clusters for each peptide- protein docking simulation. The model with the lowest score and/or the lowest binding energy (VdW, Electrostatic and Desolvation) from each run was selected for MD simulation. They display different scores between deamidated and normal peptides. Among the resulting conformations from the Autodock CG simulations, the selected one correspond to the complexes with the lowest binding energy if considering peptide 111-130; instead, for peptide 151-170, the chosen conformation results the second in terms of binding energy but the first in terms of cluster numerosity, since the lowest binding energy conformation displays a backward orientation of the peptide. Haddock docking simulations suggested a higher affinity for normal peptides than for deamidated ones. Autodock CG application display a preference for A or B isoforms by deamidated peptides 111-130 and 151-170, respectively; on the contrary, normal peptides show an inverted preference for Cxcr3 isoforms. Given that our aim is to evaluate the effects of deamidation on the binding mode and affinity between CXCR3 isoforms, the MD simulations of CXCR3-gliadin are on-going.