Exploiting the peptide-MHC water interface in the computer-aided design ofnon-natural peptides that bind to the class I MHC molecule HLA-A2

Class I major histocompatibility complex (MHC) molecules bind peptides deri ved from intracellular proteins and present them to cytotoxic T cells. Cert ain human immunological diseases are associated with errors in this process . Here we describe an approach to the design of non-natural peptides that c ould potentially interfere with peptide presentation associated with autoim mune diseases. We have shown previously that the interaction of the peptide GILGFVFTL with the MHC molecule HLA-A2 is mediated by a network of water m olecules. In principle, the addition of hydroxyl groups tb the peptide coul d allow for an enhanced interaction of the modified peptide with this water network. Here we illustrate this approach using a peptide having the non-n atural amino acid homoserine at position 3, GIhSGFVPTL, and also peptides i n which the C alpha(F5)-CO-NH-C alpha(V6) peptide bond is replaced by an et her, C alpha(F5) -CH(X)-O-C alpha(V6), to give the non-natural peptide GILG F-CH(X)-O-VFTL, where X = CH2OH or CH3. In a 200 ps solvated molecular dyna mics simulation of the HLA-A2 complexes of each peptide for GIhSGFVFTL and GILGF-CH(CH2OH)-O -VFTL the peptide conformation remained essentially uncha nged from that of GILGFVFTL in the X-ray structure of its complex with HLA- A2. In contrast, for GILGF-CH(CH3)-O -VFTL the peptide conformation deviate d from the X-ray conformation, indicating the importance of the hydroxyl gr oup.