Peptide binding specificities of HLA-B*5701 and B*5801.

Recently, genome wide association studies showed that there is a strong association between abacavir-induced serious, idiosyncratic, adverse drug reactions (ADRs) and human leukocyte antigen-B*5701 (HLA-B*5701). Studies also found that abacavir-induced ADRs were seldom observed in patients carrying the HLA-B*5801 subtype. HLA-B*5801 of the same serotype (B17) as B*5701 differs by only 4 amino acids from B*5701. It is believed that because of these sequence differences, HLA-B*5801 cannot bind the specific peptides which are required for HLA-B*5701 to stimulate the T cell immune response. Thus, the difference in peptide binding profiles between HLA-B*5701 and B*5801 is an important clue for exploring the mechanisms of abacavir-induced ADRs. VHSE (principal component score vector of hydrophobic, steric, and electronic properties), a set of amino acid structural descriptors, was employed to establish QSAR models of peptide-binding affinities of HLA-B*5701 and B*5801. Optimal linear SVM (support vector machine) models with high predictive capabilities were obtained for both B*5701 and B*5801. The R(2) (coefficient of determination), Q(2) (cross-validated R(2)), and R(PRE)(2) (R(2) of test set) of two optimal models were 0.7530, 0.7037, 0.6153 (B*5701) and 0.6074, 0.5966, 0.5762 (B*5801), respectively. For B*5701 and B*5801, the mutations in positions 45 (MET-THR) and 46 (ALA-GLU) have little influence on the selection specificity of the P2 position of the bound peptide. However, the mutation in position 97 (VAL-ARG) greatly influences the selection specificity of the P7 position. HLA-B*5701 prefers the bulky and positively charged amino acids at the P7 position. In contrast, HLA-B*5801 prefers the non-polar hydrophobic amino acids at the P7 position while positively charged amino acids are unfavored.