By recognizing members in the tumor necrosis factor (TNF) receptor superfamily, TNF ligand proteins function as extracellular cytokines to activate various signaling pathways involved in inflammation, proliferation, and apoptosis. Most ligands in TNF superfamily are trimeric and can simultaneously bind to three receptors on cell surfaces. It has been experimentally observed that the formation of these molecular complexes further triggers the oligomerization of TNF receptors, which in turn regulate the intracellular signaling processes by providing transient compartmentalization in the membrane proximal regions of cytoplasm. In order to decode the molecular mechanisms of oligomerization in TNF receptor superfamily, we developed a new computational method that can physically simulate the spatial-temporal process of binding between TNF ligands and their receptors. The simulations show that the TNF receptors can be organized into hexagonal oligomers. The formation of this spatial pattern is highly dependent not only on the molecular properties such as the affinities of trans and cis binding, but also on the cellular factors such as the concentration of TNF ligands in the extracellular area or the density of TNF receptors on cell surfaces. Moreover, our model suggests that if TNF receptors are pre-organized into dimers before ligand binding, these lateral interactions between receptor monomers can play a positive role in stabilizing the ligand-receptor interactions, as well as in regulating the kinetics of receptor oligomerization. Altogether, this method throws lights on the mechanisms of TNF ligand-receptor interactions in cellular environments.

通过识别肿瘤坏死因子（TNF）受体超家族的成员，TNF配体蛋白可作为细胞外细胞因子发挥作用，从而激活涉及炎症，增殖和凋亡的各种信号通路。TNF超家族中的大多数配体都是三聚体，可以同时与细胞表面的三个受体结合。实验上已经观察到，这些分子复合物的形成进一步触发了TNF受体的寡聚化，进而通过在细胞质的膜近端区域提供暂时的间隔化来调节细胞内信号传导过程。为了解释TNF受体超家族中寡聚的分子机制，我们开发了一种新的计算方法，可以物理模拟TNF配体及其受体之间结合的时空过程。模拟显示，TNF受体可以组织成六边形寡聚物。这种空间模式的形成不仅高度依赖于分子性质，例如反式和顺式结合的亲和力，还高度依赖于细胞因素，例如细胞外区域中TNF配体的浓度或细胞上TNF受体的密度。表面。此外，我们的模型表明，如果TNF受体在配体结合之前预先组织成二聚体，则受体单体之间的这些侧向相互作用可以在稳定配体-受体相互作用以及调节受体低聚动力学方面发挥积极作用。共，