肿瘤坏死因子与其受体相互作用的计算机模拟研究

The computer simulation study on the interaction between TNF and its receptors

利用同源模建方法,以肿瘤坏死因子(TNF)R55受体胞外区的晶体结构为参考模板,预测了TNFR75受体胞外区Cys18-Phe147片段的三维结构。根据R55受体胞外区与LT相结合的复合物的晶体结构,预测了TNF与R55及R75胞外区的复合物的三维结构,模拟了TNF与受体之间的相互作用。由于TNF与受体的作用形式是三聚体对三聚体,因此在模拟TNF与受体相互作用时选择了包括一个非对称的TNF三聚体和一个受体(R55或R75)单体的模拟系统。结合已有的突变体实验结果,利用计算机分析手段,发现了一些TNF突变体之所以具有受体选择性的三维结构基础和发挥了关键作用的氨基酸残基以及这些残基之间的主要作用形式。研究深化了对已有的突变体实验结果的认识,建立了不同的实验结果之间的内在关联,为以后有目的的新型突变体设计和实验研究打下了基础。

Based on the known crystal structure of the extracellular region of TNF receptor R55, the model structure of the extracellular domain (Cysl8-Phel47) of the other TNF receptor-R75, have been built by using of ho-mology modeling method. The complex model of TNF with its two receptors are also been constructed, according to the crystal structure of R55-lymphotoxin complex. And the interaction between TNF and receptors are studied using computer simulation technique. Because the active interaction form of TNF and receptors are trimer, a simulation systems including a TNF trimer and a receptor monomer (R55 or R75) is used. The crucial structural environment and the key residues and their explicit interaction pattern, that govern the discrimination of TNF between the R55 and R75 receptors, are determined with the relation to the mutagenesis results. The research carry out deep and new insight to the mutagenesis phenomena published previously, and make a correlation between different mutations, which will put important function in the new mutant design and mutation experiments.