Molecular dynamics analysis of the binding of human interleukin-6 with interleukin-6 α-receptor

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

doi:10.1002/prot.26002

Title: Molecular dynamics analysis of the binding of human interleukin-6 with interleukin-6 α-receptor

Journal Article · Wed Sep 16 00:00:00 EDT 2020 · Proteins

DOI:https://doi.org/10.1002/prot.26002· OSTI ID:1785215

^[1]; Ha, Khanh ^[2]; Agarwal, Rupesh ^[1]; Quarles, Darryl ^[3];

^[1]

Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)
Univ. of Tennessee Health Science Center (UTHSC), Memphis, TN (United States)

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. In this work, 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.

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Research Organization:: Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1785215

Journal Information:: Proteins, Vol. 89, Issue 2; ISSN 0887-3585

Publisher:: WileyCopyright Statement

Country of Publication:: United States

Language:: English

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aromatic stacking
hIL-6
hIL-6/IL-6Rα
hydrophobic contacts
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salt bridge

Title: Molecular dynamics analysis of the binding of human interleukin-6 with interleukin-6 α-receptor

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