Human interleukin‐6 (hIL‐6) is a multifunctional cytokine that regulates immune and inflammatory responses in addition to metabolic and regenerative processes and cancer. hIL‐6 binding to the IL‐6 receptor (IL‐6Rα) induces homodimerization and recruitment of the glycoprotein (gp130) to form a hexameric signaling complex. Anti‐IL‐6 and IL‐6R antibodies are clinically approved inhibitors of IL‐6 signaling pathway for treating rheumatoid arthritis and Castleman's disease, respectively. There is a potential to develop novel small molecule IL‐6 antagonists derived from understanding the structural basis for IL‐6/IL‐6Rα interactions. Here, we combine homology modeling with extensive molecular dynamics (MD) simulations to examine the association of hIL‐6 with IL‐6Rα. A comparison with MD of apo hIL‐6 reveals that the binding of hIL‐6 to IL‐6Rα induces structural and dynamic rearrangements in the AB loop region of hIL‐6, disrupting intraprotein contacts and increasing the flexibility of residues 48 to 58 of the AB loop. In contrast, due to the involvement of residues 59 to 78 in forming contacts with the receptor, these residues of the AB loop are observed to rigidify in the presence of the receptor. The binary complex is primarily stabilized by two pairs of salt bridges, Arg181 (hIL‐6)‐ Glu182 (IL‐6Rα) and Arg184 (hIL‐6)‐ Glu183 (IL‐6Rα) as well as hydrophobic and aromatic stacking interactions mediated essentially by Phe residues in both proteins. An interplay of electrostatic, hydrophobic, hydrogen bonding, and aromatic stacking interactions facilitates the formation of the hIL‐6/IL‐6Rα complex.

中文翻译：

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人白细胞介素6与白细胞介素6α受体结合的分子动力学分析。

人白介素-6（hIL-6）是一种多功能细胞因子，除了代谢，再生过程和癌症外，还可以调节免疫和炎症反应。hIL-6与IL-6受体（IL-6Rα）的结合诱导糖蛋白（gp130）的同二聚化和募集，从而形成六聚体信号复合物。抗IL-6和IL-6R抗体是分别被批准用于治疗类风湿关节炎和Castleman病的IL-6信号通路抑制剂。通过了解IL-6 /IL-6Rα相互作用的结构基础，有可能开发新型的小分子IL-6拮抗剂。在这里，我们将同源性建模与广泛的分子动力学（MD）模拟相结合，以检查hIL-6与IL-6Rα的关联。与载脂蛋白hIL-6的MD的比较表明，hIL-6与IL-6Rα的结合可诱导hIL-6的AB环区域发生结构和动态重排，破坏蛋白内接触并增加其48-58位残基的柔性。 AB循环。相反，由于残基59至78参与与受体形成接触，因此观察到AB环的这些残基在存在受体时硬化。二元配合物主要通过两对盐桥Arg181（hIL-6）-Glu182（IL-6Rα）和Arg184（hIL-6）-Glu183（IL-6Rα）以及基本介导的疏水和芳族堆积相互作用来稳定两种蛋白质中的Phe残基都存在 静电，疏水，氢键和芳族堆积相互作用的相互作用促进了hIL-6 /IL-6Rα复合物的形成。