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 q2 = 0.683 and r2 = 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 pIC50 (-logIC50) 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/ < or = 0.5 log unit; 29.3% with 1.0 < or = /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.
Doytchinova
Irini A
IA
Edward Jenner Institute for Vaccine Research, Compton, Berkshire, United Kingdom. irini.doytchinova@jenner.ac.uk
Flower
Darren R
DR
D000595:Amino Acid Sequence; D015234:HLA-A Antigens / Q000378:metabolism*; D015789:HLA-A2 Antigen; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D021621:Imaging, Three-Dimensional; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity
D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010455:Peptides