Mahmood M D Iqbal, Matsuo Yuri, Neya Saburo, Hoshino Tyuji
Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
Chem Pharm Bull (Tokyo). 2011;59(10):1254-62. doi: 10.1248/cpb.59.1254.
Immunological response induced by small amino peptide has attracted much recent attention in the field of immunotherapy. Wilms' tumor (WT1) protein is one of the potent tumor antigens inducing immunological response in mouse and human, because WT1 is over expressed in many types of leukemia and various kinds of solid tumors. A 9-mer peptide encoded in WT1 protein (CMTWNQMNL; amino acid 235-243) is known to serve as antigenic peptide for human leukocyte antigen (HLA)-A2402 molecule. It was reported that the replacement of the second amino residue, which is deeply responsible for the peptide binding to HLA, induced strong immunological response compared to the natural peptide. In this study, 19 kinds of single amino substitutions were introduced at position 2 of this 9-mer WT1 peptide. We performed molecular dynamics simulation on the complex of each of WT1 epitope peptides and HLA-β2 micro globulin (β2m) molecule, and subsequently estimated the binding affinity using molecular mechanics/generalized-Born surface area method combined with normal mode analysis. Our computation indicated that the peptide containing M2Y or M2W mutation showed high binding affinity to the HLA-β2m molecule as well as the natural peptide. We have also examined the role of the residue at position 2 in peptide binding to HLA-β2m. The calculation showed that van der Waals interaction between the side chain of the residue at position 2 and hydrophobic residues inside B-pocket of HLA are important. These findings will be helpful to search other potent peptides that will enhance strong immunological response specific to HLA-A2402 molecule.
小氨基酸肽诱导的免疫反应最近在免疫治疗领域备受关注。威尔姆斯瘤（WT1）蛋白是在小鼠和人类中诱导免疫反应的强效肿瘤抗原之一，因为WT1在多种白血病和各类实体瘤中过度表达。已知WT1蛋白中编码的一种9聚体肽（CMTWNQMNL；氨基酸235 - 243）可作为人类白细胞抗原（HLA）-A2402分子的抗原肽。据报道，与天然肽相比，对与HLA结合起关键作用的第二个氨基酸残基进行替换可诱导强烈的免疫反应。在本研究中，在这种9聚体WT1肽的第2位引入了19种单氨基酸替换。我们对每种WT1表位肽与HLA-β2微球蛋白（β2m）分子的复合物进行了分子动力学模拟，随后使用分子力学/广义玻恩表面积法结合正常模式分析来估计结合亲和力。我们的计算表明，含有M2Y或M2W突变的肽与HLA-β2m分子以及天然肽具有高结合亲和力。我们还研究了第2位残基在肽与HLA-β2m结合中的作用。计算表明，第2位残基的侧链与HLA的B口袋内疏水残基之间的范德华相互作用很重要。这些发现将有助于寻找其他能增强针对HLA-A2402分子的强烈免疫反应的强效肽。
