SCHEME FOR RANKING POTENTIAL HLA-A2 BINDING PEPTIDES BASED ON INDEPENDENT BINDING OF INDIVIDUAL PEPTIDE SIDE-CHAINS

A method to predict the relative binding strengths of all possible non apeptides to the MHC class I molecule HLA-A2 has been developed based on experimental peptide binding data. These data indicate that, for mo st peptides, each side-chain of the peptide contributes a certain amou nt to the stability of the HLA-A2 complex that is independent of the s equence of the peptide. To quantify these contributions, the binding d ata from a set of 154 peptides were combined together to generate a ta ble containing 180 coefficients (20 amino acids X 9 positions), each o f which represents the contribution of one particular amino acid resid ue at a specified position within the peptide to binding to HLA-A2. Ei ghty peptides formed stable HLA-A2 complexes, as assessed by measuring the rate of dissociation of beta2m. The remaining 74 peptides formed complexes that had a half-life of beta2m dissociation of less than 5 m in at 37-degrees-C, or did not bind to HLA-A2, and were included becau se they could be used to constrain the values of some of the coefficie nts. The ''theoretical'' binding stability (calculated by multiplying together the corresponding coefficients) matched the experimental bind ing stability to within a factor of 5. The coefficients were then used to calculate the theoretical binding stability for all the previously identified self or antigenic nonamer peptides known to bind to HLA-A2 . The binding stability for all other nonamer peptides that could be g enerated from the proteins from which these peptides were derived was also predicted. In every case, the previously described HLA-A2 binding peptides were ranked in the top 2% of all possible nonamers for each source protein. Therefore, most biologically relevant nonamer peptides should be identifiable using the table of coefficients. We conclude t hat the side-chains of most nonamer peptides to the first approximatio n bind independently of one another to the HLA-A2 molecule.