Molecular dynamics simulation of MHC-peptide complexes as a tool for predicting potential T cell epitopes

The class I major histocompatibility complex-encoded HLA-B*2705 protein was simulated in complex with six different peptides exhibiting unexpected structure-activity relationships. Various structural and dynamical properties of the solvated protein-peptide complexes (atomic fluctuations, solvent-accessible surface areas, hydrogen bonding pattern) were found to be in qualitative agreement with the available binding data. Peptides that have been experimentally shown to bind to the protein remained tightly anchored to the MHC molecule, whereas nonbinders were significantly more weakly complexes to the protein and progressively dissociate from it at their N- and C-terminal ends. The molecular dynamics simulations emphasize the unexpectedly important role of secondary anchors (positions 1 and 3) in influencing the MHC-bound conformation of antigenic nonapeptides. Furthermore, it confirms that dominant anchor residues cannot solely account for peptide binding to a class I MHC molecule. The molecular dynamics method could be used as a complementary tool to T cell epitope predictions from the primary sequences of proteins of immunological interest. It is better suited to MHC proteins for which a crystal structure already exists. Furthermore, it may facilitate the engineering of T cell epitopes as well as the rational design of new MHC inhibitors designed to fit optimally the peptide binding cleft.