The influence of sequence microvariation among HLA-DR3 alleles on their structure and complex formation with presentation peptides

The three-dimensional structure of human leukocyte antigens HLA-DR*0301 and HLA-DR*0302 have been calculated using the homology modeling approach. Gen eral structural features of our models are similar to those of related HLA molecules. The typical layout of segments of the secondary structure is wel l preserved. However polypeptide chains are less tightly bound, which cause s slightly broader opening of the binding groove. It also results in the mo dified layout of pockets in the binding groove. Amino acids defining the re stricted sequence diversity of the proteins studied are easily available fo r interactions with ligands. A set of docking simulations was performed using modeled structures of both HLA molecules and various specific peptide ligands. The control docking of influenza hemagglutinin peptide into the HLA-DR*0101 molecule gives a comp lex structure which is in good agreement with that from crystallographic st udies. The extensive analysis of the structure of modeled complexes of HLA- DR*0301 and HLA-DR*0302 with various ligands indicates that sequence microv ariation of both alleles does not directly control the binding specificity. Preferences for binding of specific ligands, as evaluated from interaction s in modeled complexes, agree qualitatively with experimental observations. Thus, the computer aided docking simulations can be successfully used to c alculate the three-dimensional structure of HLA-ligand complexes. However, a detailed explanation of binding specificity cannot be given using present ly available modeling procedures.