Department of Biology, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran.
Department of Biology, Faculty of Basic Sciences, Shahrekord University, Shahrekord, Iran; Nanotechnology Research Center, Shahrekord University, Shahrekord, Iran.
J Mol Graph Model. 2022 Mar;111:108079. doi: 10.1016/j.jmgm.2021.108079. Epub 2021 Nov 16.
Multiple sclerosis is recognized as a chronic inflammatory disease. Human leukocyte antigen (HLA) plays an important role in initiating adaptive immune responses. HLA class I is present in almost all nucleated cells and presents the cleaved endogenous peptide antigens to cytotoxic T cells. HLA-A03 is one of the HLA class I alleles, which is reported as substantially related HLA to MS disease. In 2011, the structure of the HLA-A03 in complex was identified with an immunodominant proteolipid protein (PLP) epitope (KLIETYFSK). This complex has been reported as an important autoantigen-presenting complex in MS pathogenesis. In this study, new peptides were designed to bind to this complex that may prevent specific pathogenic cytotoxic T cell binding to this autoantigen-presenting complex and CNS demyelination. Herein, 14 new helical peptides containing 19 amino acids were designed and their structures were predicted using the PEP-FOLD server. The binding of each designed peptide to the mentioned complex was then performed. A mutation approach was used by the BeAtMuSiC server to improve the binding affinity of the designed peptide. In each position, amino acid substitutions leading to an increase in the binding affinity of the peptide to the mentioned complex were determined. Finally, the resulting complexes were simulated for 40 ns using AMBER18 software. The results revealed that out of 14 designed peptides, "WRYWWKDWAKQFRQFYRWF" peptide exhibited the highest affinity for binding to the mentioned complex. This peptide can be considered as a potential drug to control multiple sclerosis disease in patients carrying the HLA-A*03 allele.
多发性硬化症被认为是一种慢性炎症性疾病。人类白细胞抗原（HLA）在启动适应性免疫反应中起着重要作用。HLA Ⅰ类存在于几乎所有有核细胞中，并将切割的内源性肽抗原呈递给细胞毒性 T 细胞。HLA-A03 是 HLA Ⅰ类等位基因之一，据报道与 MS 疾病有很大关系。2011 年，鉴定了与免疫优势蛋白脂蛋白（PLP）表位（KLIETYFSK）结合的 HLA-A03 结构。该复合物已被报道为 MS 发病机制中重要的自身抗原呈递复合物。在这项研究中，设计了新的肽来结合该复合物，可能防止特定的致病性细胞毒性 T 细胞与该自身抗原呈递复合物和中枢神经系统脱髓鞘结合。在此，设计了 14 个新的含有 19 个氨基酸的螺旋肽，并使用 PEP-FOLD 服务器预测了它们的结构。然后对每个设计肽与所述复合物的结合进行了测试。BeAtMuSiC 服务器使用突变方法来提高设计肽与所述复合物的结合亲和力。在每个位置，确定导致肽与所述复合物的结合亲和力增加的氨基酸取代。最后，使用 AMBER18 软件对所得复合物进行了 40 ns 的模拟。结果表明，在 14 个设计肽中，“WRYWWKDWAKQFRQFYRWF”肽与所述复合物的结合亲和力最高。该肽可以被认为是一种控制携带 HLA-A*03 等位基因的患者多发性硬化症的潜在药物。
