Molecular Dynamics Analysis of The Binding of Human Interleukin-6 with Interleukin-6 α-Receptor.

Gupta, Madhulika; Ha, Khanh; Agarwal, Rupesh; Quarles, L Darryl; Smith, Jeremy C

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 signalling complex. Anti-IL-6 and IL-6R antibodies are clinically approved inhibitors of IL-6 signalling 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 modelling 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 intra-protein contacts and increasing the flexibility of residues 48-58 of the AB loop. In contrast, due to the involvement of residues 59-78 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. This article is protected by copyright. All rights reserved.