The Tumor Necrosis Factor (TNF) and the TNF receptor (TNFR) superfamilies are composed of 19 ligands and 30 receptors, respectively. The oligomeric properties of ligands, both membrane bound and soluble, has been studied most. However, less is known about the oligomeric properties of TNFRs. Earlier reports identified the extracellular, membrane-distal, cysteine-rich domain as a pre-ligand assembly domain which stabilizes receptor dimers and/or trimers in the absence of ligand. Nevertheless, recent reports based on structural nuclear magnetic resonance (NMR) highlight the intrinsic role of the transmembrane domains to form dimers (p75NTR), trimers (Fas), or dimers of trimers (DR5). Thus, understanding the structural basis of transmembrane oligomerization may shed light on the mechanism for signal transduction and the impact of disease-associated mutations in this region. To this end, here we used an in silico coarse grained molecular dynamics approach with Martini force field to study TNFR transmembrane homotypic interactions. We have first validated this approach studying the three TNFR described by NMR (p75NTR, Fas, and DR5). We have simulated membrane patches composed of 36 helices of the same receptor equidistantly distributed in order to get unbiassed information on spontaneous proteins assemblies. Good agreement was found in the specific residues involved in homotypic interactions and we were able to observe dimers, trimers, and higher-order oligomers corresponding to those reported in NMR experiments. We have, applied this approach to study the assembly of disease-related mutations being able to assess their impact on oligomerization stability. In conclusion, our results showed the usefulness of coarse grained simulations with Martini force field to study in an unbiased manner higher order transmembrane oligomerization.

肿瘤坏死因子（TNF）和TNF受体（TNFR）超家族分别由19个配体和30个受体组成。膜结合的和可溶的配体的低聚性质已被研究最多。然而，关于TNFR的寡聚性质的了解较少。较早的报道将细胞外，膜远端，富含半胱氨酸的结构域确定为配体前组装结构域，该结构域在不存在配体的情况下稳定受体二聚体和/或三聚体。然而，基于结构核磁共振（NMR）的最新报道强调了跨膜结构域形成二聚体（p75NTR），三聚体（Fas）或三聚体（DR5）的内在作用。从而，了解跨膜低聚的结构基础可能会阐明该区域的信号转导机制和疾病相关突变的影响。为此，我们在此处使用了在计算机上马蒂尼力场的粗粒分子动力学方法研究TNFR跨膜同型相互作用。我们首先通过研究NMR描述的三种TNFR（p75NTR，Fas和DR5）验证了这种方法。我们已经模拟了由等距分布的36个相同受体螺旋组成的膜片，以便获得有关自发蛋白质组装体的无偏信息。在同型相互作用中涉及的特定残基中发现了很好的一致性，并且我们能够观察到与NMR实验中报道的那些相对应的二聚体，三聚体和更高阶的低聚物。我们已经采用这种方法来研究疾病相关突变的组装，从而能够评估其对寡聚稳定性的影响。结论，