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 | ≤ 0.5 log unit; 29.3% with 1.0 ≤ | residuals | < 0.5; and 7.5% with | residuals | > 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. Proteins 2002;48:505–518. © 2002 Wiley‐Liss, Inc.