The interactions between tumor necrosis factors (TNFs) and their corresponding receptors (TNFRs) play a pivotal role in inflammatory responses. Upon ligand binding, TNFR receptors were found to form oligomers on cell surfaces. However, the underlying mechanism of oligomerization is not fully understood. In order to tackle this problem, molecular dynamics (MD) simulations have been applied to the complex between TNF receptor-1 (TNFR1) and its ligand TNF-α as a specific test system. The simulations on both all-atom (AA) and coarse-grained (CG) levels achieved the similar results that the extracellular domains of TNFR1 can undergo large fluctuations on plasma membrane, while the dynamics of TNFα-TNFR1 complex is much more constrained. Using the CG model with the Martini force field, we are able to simulate the systems that contain multiple TNFα-TNFR1 complexes with the timescale of microseconds. We found that complexes can aggregate into oligomers on the plasma membrane through the lateral interactions between receptors at the end of the CG simulations. We suggest that this spatial organization is essential to the efficiency of signal transduction for ligands that belong to the TNF superfamily. We further show that the aggregation of two complexes is initiated by the association between the N-terminal domains of TNFR1 receptors. Interestingly, the cis-interfaces between N-terminal regions of two TNF receptors have been observed in the previous X-ray crystallographic experiment. Therefore, we provide supportive evidence that cis-interface is of functional importance in triggering the receptor oligomerization. Taken together, our study brings insights to understand the molecular mechanism of TNF signaling.

中文翻译：

---

质膜上TNF受体低聚的计算模拟。

肿瘤坏死因子（TNFs）及其相应的受体（TNFRs）之间的相互作用在炎症反应中起关键作用。配体结合后，发现TNFR受体在细胞表面形成寡聚物。但是，对低聚的潜在机理尚未完全了解。为了解决此问题，分子动力学（MD）模拟已作为特定的测试系统应用于TNF受体1（TNFR1）及其配体TNF-α之间的复合物。在全原子（AA）和粗粒（CG）水平上的模拟获得了相似的结果，即TNFR1的胞外域可以在质膜上经历较大的波动，而TNFα-TNFR1复合物的动力学受到更大的限制。使用CG模型和马提尼力场，我们能够以毫秒为单位模拟包含多个TNFα-TNFR1复合物的系统。我们发现，复合物可以通过CG模拟结束时受体之间的侧向相互作用在质膜上聚集为低聚物。我们建议这种空间组织对于属于TNF超家族的配体的信号转导效率至关重要。我们进一步表明，两种复合物的聚集是由TNFR1受体的N末端域之间的关联引发的。有趣的是，在先前的X射线晶体学实验中已经观察到两个TNF受体的N末端区域之间的顺式界面。因此，我们提供支持性证据表明，顺式界面在触发受体寡聚化中具有功能重要性。在一起