Computational Modeling of the Anti-Inflammatory Complexes of IL37

Interleukin (IL) 37 is an anti-inflammatory cytokine belonging to the IL1 protein family. Owing to its pivotal role in modulating immune responses, particularly through interfering with the IL18 signaling, elucidating the IL37 complex structures holds substantial therapeutic promise for various autoimmune disorders and cancers. Although the structural homology between IL37 and IL18 suggests a common binding mechanism with the primary members of IL18 signaling, the structures of IL37 complexes have not been experimentally resolvet yet. This computational study aims to address this gap through molecular modeling and classical molecular dynamics simulations, revealing the structural underpinnings of its modulatory effects on the IL18 signaling pathway. All IL37 protein-protein complexes, including both receptor-dependent and receptor-independent pairs, were modeled using a range of methods from homology modeling to AlphaFold2 multimer predictions. The models that successfully captured experimental features were subjected to molecular dynamics simulations. As positive controls, binary and ternary PDB complexes of IL18 were also included. The comparative look on the IL37 and IL18 complexes revealed a highly dynamic nature for the IL37 complexes. Repeated simulations of IL37-IL18Rα showed altered receptor conformations capable of accommodating IL37 in its dimeric form without clashes, providing a structural basis for the failure of IL18Rβ to be recruited to the IL37-IL18Rα complex. Simulations of receptor complexes involving various mature forms of IL37 revealed that the N-terminal loop of IL37 is pivotal in modulating receptor dynamics. Additionally, the glycosyl chains on the primary receptor residue N297 act as a steric block against the IL37's N-terminal loop. The interactions between IL37 and IL18BP were also investigated, and our dynamical models indicated that a homologous binding mode was unlikely, suggesting an alternative mechanism by which IL37 functions as an anti-inflammatory cytokine upon binding to IL18BP. Altogether this study accesses to the structure and dynamics of IL37 complexes, offering molecular insights into IL37's inhibitory function within the IL18 signaling pathway and informing future experimental research.