Physicochemical explanation of peptide binding to HLA-A*0201 major histocompatibility complex: A three-dimensional quantitative structure-activity relationship study

A three-dimensional quantitative structure-activity relationship method for the prediction of peptide binding affinities to the MHC class I molecule HLA-A*0201 was developed by applying the CoMSIA technique on a set of 266 peptides. To increase the self consistency of the initial CoMSIA model, the poorly predicted peptides were excluded from the training set in a stepwise manner and then included in the study as a test set. The final model, based on 236 peptides and considering the steric, electrostatic, hydrophobic, hydrogen bond donor, and hydrogen bond acceptor fields, had q(2) = 0.683 and r(2) = 0.891. The stability of this model was proven by cross-validations in two and five groups and by a bootstrap analysis of the non-cross-validated model. The residuals between the experimental pIC(50) (-logIC(50)) values and those calculated by "leave-one-out" cross-validation were analyzed. According to the best model, 63.2% of the peptides were predicted with \residuals\ less than or equal to0.5 log unit; 29.3% with 1.0 less than or equal to \residuals\ <0.5; and 7.5% with vertical bar residuals vertical bar > 1.0 log unit. The mean \residual\ value was 0.489. The coefficient contour maps identify the physicochemical property requirements at each position in the peptide molecule and suggest amino acid sequences for high-affinity binding to the HLA-A*0201 molecule.