Computational simulations of TNF receptor oligomerization on plasma membrane

Abstract

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.

Computational modelling of TNFα related pathways regulated by neuroinflammation, oxidative stress and insulin resistance in neurodegeneration

“…Elevations in concentration changes of TNFα and its receptor has also been observed in this model according to the feedback mechanism that might be attributed to diseased states as observed in previous computational models (Anderson et al 2015). Other computational models also have evidence showing increase in the extracellular TNFα and its receptor concentrations could result in negative regulation of other signaling pathways involved in inflammation and apoptosis (Fallahi-Sichani et al 2011;Su and Wu 2020). In diseased conditions, simulations showed elevations in the concentration of TNFα together with its receptor TNFR1.…”

“…Most of the initial conditions for the model parameters were assigned as relative values rather than real data. With the need to model crosstalk and critical networks relevant to neurodegeneration identified by more recent studies, we have incorporated the crosstalk between insulin resistance, oxidative stress and neuroinflammation related to TNFα signalling in normal, AD and PD conditions (Fallahi-Sichani et al 2011;Sasidharakurup et al 2020;Su and Wu 2020). The parameteric values relating to biological states and initial conditions for this model were manually extracted from literature on disease models.…”