Kumar Amit, Melis Paola, Genna Vito, Cocco Eleonora, Marrosu Maria Giovanna, Pieroni Enrico
CRS4 Biomedicine, Science and Technology Park, Piscinamanna, Pula, Italy.
Mol Biosyst. 2014 Aug;10(8):2043-54. doi: 10.1039/c4mb00203b.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that has a notably high incidence in Sardinia. Our study focuses on two HLA class II haplotypes associated with the disease in Sardinia, the rare predisposing DRB115:01-DQB106:02 and the widespread protective DRB116:01-DQB105:02. This framework enabled the highlighting of HLA binding pocket specificity and peptide recognition mechanisms by employing molecular dynamics simulations of the whole DRB1-DQB1 haplotype interacting with MBP- and EBV-derived peptides. We analyzed peptide-protein interaction networks and temporal evolution of the original complexes and after key amino acid mutations. The mutation G86V of the protective DRB1 allele exerted its effect mainly in the presence of the EBV viral peptide, with local and long range outcomes. However, the V38A mutation of the protective DQB1 showed a long range effect only in the case of the MBP myelin peptide. Our findings also demonstrate a DRB1/DQB1 complementary molecular recognition of peptides. This mechanism could provide a robust synergistic action and a differential role of DRB1 and DQB1 in tissues and in the time-steps towards autoimmunity. In addition, we demonstrate that negatively charged residues in pockets 4 and 9 play a role in MS susceptibility. Our findings are supported by recent experiments using a closely related MS animal model. Overall, our analysis confirms the role of the DRB1-DQB1 haplotype in conferring disease predisposition and could provide a valuable aid in designing optimal therapeutic peptides for MS therapy.
多发性硬化症（MS）是一种中枢神经系统的自身免疫性疾病，在撒丁岛的发病率显著较高。我们的研究聚焦于撒丁岛与该疾病相关的两种HLA II类单倍型，即罕见的易感型DRB115:01 - DQB106:02和广泛存在的保护型DRB116:01 - DQB105:02。通过对整个DRB1 - DQB1单倍型与髓鞘碱性蛋白（MBP）和EB病毒衍生肽相互作用进行分子动力学模拟，该框架能够突出HLA结合口袋特异性和肽识别机制。我们分析了原始复合物以及关键氨基酸突变后的肽 - 蛋白质相互作用网络和时间演变。保护性DRB1等位基因的G86V突变主要在EB病毒肽存在时发挥作用，具有局部和远距离效应。然而，保护性DQB1的V38A突变仅在MBP髓鞘肽的情况下显示出远距离效应。我们的研究结果还证明了DRB1/DQB1对肽的互补分子识别。这种机制可以提供强大的协同作用以及DRB1和DQB1在组织中以及自身免疫发展的时间步长中的不同作用。此外，我们证明口袋4和9中的带负电荷残基在MS易感性中起作用。我们的研究结果得到了使用密切相关的MS动物模型的近期实验的支持。总体而言，我们的分析证实了DRB1 - DQB1单倍型在赋予疾病易感性方面的作用，并可为设计用于MS治疗的最佳治疗性肽提供有价值的帮助。
