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 (&lo 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
energyminimized 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 a-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 Nterminal 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,
energyminimized 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
a-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 a-helical conformation for the bound peptide