RATIONAL DESIGN OF NONNATURAL PEPTIDES AS HIGH-AFFINITY LIGANDS FOR THE HLA-B-ASTERISK-2705 HUMAN-LEUKOCYTE ANTIGEN

From the three-dimensional structure of the class I major histocompati bility complex (MHC) HLA-B82705 protein, several nonnatural peptides w ere designed either to optimize the interactions of one peptide amino acid (position 3) with its HLA binding pocket (pocket D) or to simplif y the T-cell receptor-binding part by substitution with organic spacer s. The stability of each MHC-ligand complex was simulated by 150-ps mo lecular dynamics in a water environment and compared with that of the natural complexes. All peptides were synthesized and tested for bindin g to the class I MHC protein in an in vitro assembly assay. As predict ed from the computed atomic fluctuations and buried surface areas of M HC-bound ligands, bulky hydrophobic side chains at position 3 enhance the binding of a nonameric peptide to the KLA-B27 protein. Furthermore , it was possible to simplify half of the peptide sequence (residues 4 -8) by replacement with organic fragments without altering the affinit y of the designed ligands for the class I MHC protein. This study cons titutes an initial step toward the rational design of nonpeptide class I MHC ligands for use in the selective immunotherapy of autoimmune di seases associated with particular HLA alleles.