Data_Sheet_1_Molecular Simulation of Oncostatin M and Receptor (OSM–OSMR) Interaction as a Potential Therapeutic Target for Inflammatory Bowel Disease.pdf

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.

以制瘤素M（oncostatin M, OSM）介导的炎症为靶点的治疗策略，是治疗炎症性肠病（inflammatory bowel disease, IBD）的潜在方案。尽管已有研究探索OSM与其受体（OSMR）的相互作用在IBD发病机制中的具体作用，但OSM-OSMR复合物的三维结构仍未明确。本研究通过计算模拟方法，在原子层面预测了OSM与OSMR的相互作用模式：采用同源建模法构建OSMR的相互作用结构域；通过分子对接获得OSM-OSMR复合物的近天然构象，并进一步在显式溶剂体系中开展长时间尺度的分子动力学（MD）模拟，以采样OSM结合OSMR时的构象空间。待模拟体系达到平衡态后，计算单残基能量贡献以表征参与OSM-OSMR复合物形成的关键残基。基于上述关键残基，通过计算丙氨酸突变分析鉴定出8个“热点残基”（OSM：Arg100、Leu103、Phe160及Gln161；OSMR：Tyr214、Ser223、Asp262及Trp267），并通过对鉴定出的热点残基之一R100A的突变体开展额外MD模拟验证了该结论。此外，通过FTMap分析在OSM-OSMR结合界面检测到6个空腔，提示其为重要的结合位点。本研究预测的OSM-OSMR复合物三维结构，以及构成结合界面核心的鉴定热点残基，为理解OSM与OSMR的相互作用提供了有益参考，而检测到的空腔则可作为设计小分子以阻断该相互作用的潜在靶点。