Structure-based prediction of MHC–peptide association: Algorithm comparison and application to cancer vaccine design

Peptide vaccination for cancer immunotherapy requires identification of peptide epitopes derived from antigenic proteins associated with the tumor. Such peptides can bind to MHC proteins (MHC molecules) on the tumor-cell surface, with the potential to initiate a host immune response against the tumor. Computer prediction of peptide epitopes can be based on known motifs for peptide sequences that bind to a certain MHC molecule, on algorithms using experimental data as a training set, or on structure-based approaches. We have developed an algorithm, which we refer to as PePSSI, for flexible structural prediction of peptide binding to MHC molecules. Here, we have applied this algorithm to identify peptide epitopes (of nine amino acids, the common length) from the sequence of the cancer-testis antigen KU-CT-1, based on the potential of these peptides to bind to the human MHC molecule HLA-A2. We compared the PePSSI predictions with those of other algorithms and found that several peptides predicted to be strong HLA-A2 binders by PePSSI were similarly predicted by another structure-based algorithm, PREDEP. The results show how structure-based prediction can identify potential peptide epitopes without known binding motifs and suggest that side chain orientation in binding peptides may be obtained using PePSSI.