Molecular Simulation of Oncostatin M and Receptor (OSM–OSMR) Interaction as a Potential Therapeutic Target for Inflammatory Bowel Disease

Abstract

Therapeutics targeting cytokines such as the oncostatin M (OSM)-mediated inflammation represent a potential strategy for the treatment of inflammatory bowel disease (IBD). Despite the investigation of the specific role of the interactions between OSM and the receptor (OSMR) in IBD pathogenesis, the 3D structure of the OSM-OSMR complex remains elusive. In this work, the interaction mode between OSM and OSMR at atomic level was predicted by computational simulation approach. The interaction domain of the OSMR was built with the homology modeling method. The near-native structure of the OSM-OSMR complex was obtained by docking, and long-time scale molecular dynamics (MD) simulation in an explicit solvent was further performed to sample the conformations when OSM binds to the OSMR. After getting the equilibrated states of the simulation system, per-residue energy contribution was calculated to characterize the important residues for the OSM-OSMR complex formation. Based on these important residues, eight residues (OSM: Arg100, Leu103, Phe160, and Gln161; OSMR: Tyr214, Ser223, Asp262, and Trp267) were identified as the "hot spots" through computational alanine mutagenesis analysis and verified by additional MD simulation of R100A (one of the identified "hotspots") mutant. Moreover, six cavities were detected at the OSM-OSMR interface through the FTMap analysis, and they were suggested as important binding sites. The predicted 3D structure of the OSM-OSMR complex and the identified "hot spots" constituting the core of the binding interface provide helpful information in understanding the OSM-OSMR interactions, and the detected sites serve as promising targets in designing small molecules to block the interactions.

Computational design and modeling of nanobodies toward SARS‐CoV‐2 receptor binding domain

“…We use the MM/GBSA method (Kollman et al., 2000), which has been widely employed to characterize the thermodynamics properties of different types of protein–protein interactions (PPIs; Du et al., 2020; Tu et al., 2018; Wang et al., 2019), to estimate the binding affinities between Nbs and RBD. Table 1 lists the total binding free energy (Δ G tol ) as well as their compositing terms including the electrostatic interaction energy (Δ E ele ), van der Waals interaction energy (Δ E vdW ), non‐polar solvent energy (Δ G nonpol ), and polar solvent energy (Δ G pol ).…”

Exploring the Binding Interaction of Raf Kinase Inhibitory Protein With the N-Terminal of C-Raf Through Molecular Docking and Molecular Dynamics Simulation

“…Arg398 of C-Raf and Lys80 of RKIP could be regarded as "hot spot" residues along with the above previously identified interface residues and deemed to be druggable sites for future development of novel inhibitors. Using one of the identified "hot spots" as an example, a long-time scale 300 ns MD simulation was performed for the Arg398Ala mutation according to the similar strategy adopted in previous PPI study (Du et al, 2020). A noteworthy difference was noticed near the mutation site when the representative trajectory extracted at 180 ns (RMSD of 0.9 nm) was compared with the representative WT snapshot (Figure 5).…”

“…The AMBER99SB-ILDN forcefield was applied to generate the topology parameters of the structural complexes (Lindorff-Larsen et al, 2010;Venkatesan et al, 2015;Zarei, et al, 2017;Galeazzi et al, 2018). The binary complexes were then surrounded by dodecahedron periodic box of SPCE water molecules (Selent et al, 2013;Venkatesan et al, 2015;Galeazzi et al, 2018;Du et al, 2020). Cl − ions were added to the systems to neutralize it prior to minimization (Supplementary Table S1).…”

The OSMR Gene Is Involved in Hirschsprung Associated Enterocolitis Susceptibility through an Altered Downstream Signaling

“…The H187 residue is located in the region linking three hot spot sites of the OSM-OSMR binding task [19]. The change from basic histidine to polar glutamine, although not directly affecting a binding hot spot, could alter the conformation of the sites active in OSM-OSMR interaction.…”

“…The whole protein model is shown on the left, while the region around H187 is enlarged in the right, distinguishing between the wt (above) and the p.H187Q variant sequence (below). The region is further zoomed in to show the three hotspots sites around H187 reported by Du et al [19] in yellow, blue, and red, respectively, with the Tyr214 residue being the hot spot binding residue in common between the three.…”