Infection Bioengineering Group, Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, India.
Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, India.
Comput Biol Med. 2022 Sep;148:105856. doi: 10.1016/j.compbiomed.2022.105856. Epub 2022 Jul 14.
Multiple sclerosis (MS) can be induced upon successful presentation of myelin antigens by MHC I/II. Antigenic similarity between the myelin and viral proteins may worsen the immunological responses.
Antigenic regions within myelin proteins; PLP1, MBP, MOG, and MAG were analyzed using SVMTrip and EMBOSS. Homology search identified sequence similarity between the predicted host epitopes and viral proteins. NetMHCpan predicted MHC I/II binding followed by peptide-protein docking through the HPEPDOCK server. Thereafter we analyzed conformational flexibility and stability of 15 protein-peptide complexes based on high docking scores. The binding free energy was calculated using conventional (MD) and Gaussian accelerated molecular dynamics simulation.
PLP1, MBP, MAG and MOG contained numerous antigenic epitopes. MBP and MOG epitopes had sequence similarity to HHV-6 BALF5; EBNA1 and CMV glycoprotein M (gM), and EBV LMP2B, gp350/220; HHV-8 ORFs respectively. Many herpes virus proteins like tegument, envelope glycoproteins, and ORFs of EBV, CMV, HHV-6, and HHV-8 demonstrated sequence similarity with MAG and PLP1. Some antigenic peptides were also linear B-cell epitopes and influenced cytokine production by T-cell. MHC I allele HLA-B57:01 bound to PLP1 peptide and HLA-A68:02 bound to a MAG peptide strongly. MHC II alleles HLA-DRB104:05 and HLA-DR101:01 associated with MAG- and MOG-derived peptides, respectively, demonstrating high HPEPDOCK scores. MD simulations established stable binding of certain peptides with the MHC namely HLA-B51:01-MBP(DYKSAHKGFKGVDAQGTLSKIFKL), HLA-B57:01-PLP1(PDKFVGITYALTVVWLLVFACSAVPVYIYF), HLA-DR101:01-MOG(VEDPFYWVSPGVLVLLAVLPVLLLQITVGLVFLCLQYR) and HLA-DRB104:05-MAG(TWVQVSLLHFVPTREA).
Cross-reactivity between self-antigens and pathogen derived immunodominant epitopes may induce MS. Our study supported the role of specific MHC alleles as a contributing MS risk factor.
髓鞘抗原经 MHC I/II 呈递后可诱导多发性硬化（MS）。髓鞘蛋白与病毒蛋白之间的抗原相似性可能会加重免疫反应。
使用 SVMTrip 和 EMBOSS 分析髓鞘蛋白（PLP1、MBP、MOG 和 MAG）中的抗原区域。预测的宿主表位与病毒蛋白之间的同源性搜索确定了序列相似性。NetMHCpan 预测 MHC I/II 结合，然后通过 HPEPDOCK 服务器进行肽-蛋白对接。此后，我们根据高对接分数分析了 15 个蛋白-肽复合物的构象灵活性和稳定性。使用传统（MD）和高斯加速分子动力学模拟计算结合自由能。
PLP1、MBP、MAG 和 MOG 含有许多抗原表位。MBP 和 MOG 表位与 HHV-6 BALF5、EBNA1 和 CMV 糖蛋白 M（gM）以及 EBV LMP2B、gp350/220、HHV-8 ORFs 具有序列相似性。许多疱疹病毒蛋白，如包膜糖蛋白和 EBV、CMV、HHV-6 和 HHV-8 的 ORFs，与 MAG 和 PLP1 具有序列相似性。一些抗原肽也是线性 B 细胞表位，可影响 T 细胞产生细胞因子。MHC I 等位基因 HLA-B57:01 与 PLP1 肽结合，HLA-A68:02 与 MAG 肽结合较强。MHC II 等位基因 HLA-DRB104:05 和 HLA-DR101:01 分别与 MAG 和 MOG 衍生肽相关，显示出较高的 HPEPDOCK 分数。MD 模拟证实了某些与 MHC 结合的肽具有稳定性，即 HLA-B51:01-MBP（DKYSAHKGFKGVDAQGTLSKIFKL）、HLA-B57:01-PLP1（PDKFVGITYALTVVWLLVFACSAVPVYIYF）、HLA-DR101:01-MOG（VEDPFYWVSPGVLVLLAVLPVLLLQITVGLVFLCLQYR）和 HLA-DRB104:05-MAG（TWVQVSLLHFVPTREA）。
自身抗原与病原体衍生的免疫优势表位之间的交叉反应可能会引发 MS。我们的研究支持特定 MHC 等位基因作为 MS 风险因素的作用。
