Fig. 1. The multiscale simulation framework.

TNFα ligands (red) are initially presented on cell surfaces (mTNFα). They also occur as soluble variants (sTNFα) after their “stalk” regions are cleaved by metalloproteases (a). The trimeric ligands can simultaneously form “trans-interactions” with three receptors TNFR1 (green). Additionally, two TNFR1 receptors can also form a “cis-interaction”, through their PLAD regions (green dots) which do not spatially interfere with the trans-binding sites (yellow dots). It was found that the activation of TNFR1-mediated signaling pathways is more preferred by sTNFα than mTNFα, while both forms of ligands can further induce the aggregation of TNFR1 into nanoscale clusters through the combination of trans- and cis-interaction. Using a domain-based coarse-grained model and diffusion-reaction simulation algorithm, we compare the system in which clustering of TNFR1 is induced by soluble TNFα (b) to the system in which clustering is induced by membrane-bound TNFα (c).