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全基因组关联分析研究发现,abacavir的严重毒副作用具HLA-B*5701限制性,而仅在4个氨基酸位点存在差异的B*5801携带者却无明显反应,推测是由于B*5801无法结合致敏相关特异性多肽所致.因此,比较分析B*5701和B*5801的多肽亲和特性及B*5701特异性肽库是探索abacavir限制性毒副作用机理的首要内容.本文基于IEDB数据库,采用VHSE结构表征方法,建立了HLA-B*5701和B*5801多肽亲和活性的支持向量机预测模型,其最优线性模型的R2,10-fold交互验证Q2和外部预测RPRE2分别为0.7530,0.7037,0.6153(B*5701)和0.6074,0.5966,0.5762(B*5801).研究表明,位于结合凹槽B口袋附近的45(MET-THR)和46(ALA-GLU)位突变残基对B*5701和B*5801结合肽P2位的氨基酸选择特异性影响较小,二者在P2位优先选择的氨基酸种类基本一致,仅在优先选择顺序上有所差异;位于C口袋和E口袋间的97位(VAL-ARG)突变残基明显改变了P7位氨基酸的选择偏好.对于HLA-B*5701,其P7位优先选择大体积正电性氨基酸(ARG,HIS,LYS),而B*5801则优先选择非极性的疏水性氨基酸,且正电性氨基酸对结合极为不利.
Genome-wide association analysis showed that the severe side effects of abacavir were restricted by HLA-B * 5701, whereas B * 5801 carriers with only 4 amino acid residues showed no significant response, presumably due to the inability of B * 5801 to bind Therefore, comparative analysis of B * 5701 and B * 5801 peptide affinity characteristics and B * 5701 specific peptide library is to explore the abacavir restrictive toxic side effects of the primary content.In this paper, based on the IEDB database, The support vector machine (SVM) prediction model of affinity activity of HLA-B * 5701 and B * 5801 polypeptide was established by VHSE structural characterization method. R2, 10-fold cross-validation Q2 and RPRE2 of the optimal linear model were 0.7530, 0.7037,0.6153 (B * 5701) and 0.6074,0.5966,0.5762 (B * 5801) .Studies showed that the residues 45 (MET-THR) and 46 (ALA-GLU) * 5701 and B * 5801 binding amino acid selectivity of peptide P2 less specificity, the two preferred amino acid at P2 position is basically the same, only in the order of preference; located in the C pocket and E pocket The mutation at position 97 (VAL-ARG) significantly changed the amino acid preference at position P7. In HLA-B * 5701, a large positive amino acid (ARG, HIS, LYS) is preferred at position P7 while a non-polar hydrophobic amino acid is preferentially selected by B * 5801, and the positive amino acid is extremely unfavorable for binding .