Molecular modeling of an antigenic complex between a viral peptide and a class I major histocompatibility glycoprotein

Computer simulation of the conformations of short antigenic peptides (5–10 residues) either free or bound to their receptor, the major histocompatibility complex (MHC)‐encoded glycoprotein H‐2 Ld, was employed to explain experimentally determined differences in the antigenic activities within a set of related peptides. Starting for each sequence from the most probable conformations disclosed by a pattern‐recognition technique, several energy‐minimized structures were subjected to molecular dynamics simulations (MD) either in vacuo or solvated by water molecules. Notably, antigenic potencies were found to correlate to the peptides propensity to form and maintain an overall α‐helical conformation through regular i,i+4 hydrogen bonds. Accordingly, less active or inactive peptides showed a strong tendency to form i,i+3 hydrogen bonds at their N‐terminal end. Experimental data documented that the C‐terminal residue is critical for interaction of the peptide with H‐2 Ld. This finding could be satisfactorily explained by a 3‐D Q.S.A.R. analysis postulating interactions between ligand and receptor by hydrophobic forces. A 3‐D model is proposed for the complex between a high‐affinity nonapeptide and the H‐2 Ld receptor. First, the H‐2 Ld molecule was built from X‐ray coordinates of two homologous proteins: HLA‐A2 and HLA‐Aw68, energy‐minimized and studied by MD simulations. With HLA‐A2 as template, the only realistic simulation was achieved for a solvated model with minor deviations of the MD mean structure from the X‐ray conformation. Water simulation of the H‐2 Ld protein in complex with the antigenic nonapeptide was then achieved with the template‐derived optimal parameters. The bound peptide retains mainly its α‐helical conformation and binds to hydrophobic residues of H‐2 Ld that correspond to highly polymorphic positions of MHC proteins. The orientation of the nonapeptide in the binding cleft is in accordance with the experimentally determined distribution of its MHC receptor‐binding residues (agretope residues). Thus, computer simulation was successfully employed to explain functional data and predicts α‐helical conformation for the bound peptide. © 1992 Wiley‐Liss, Inc.