Title: Stabilizing Interactions In TNF Ligand-receptor Binding
Abstract: High-affinity binding of extracellular protein ligands belonging to the tumor necrosis factor (TNF) superfamily to their conjugate transmembrane cell surface TNF receptors initiates the extrinsic signaling cascade that results in apoptotic cell death. Intriguingly, despite a high-degree of structural homology among the family of ligands and receptors, the ligand binding is both high-affinity and has high-specificity. As yet, it is poorly understood what confers this specificity. Starting from the crystal structures for the TRAIL-death receptor 5 and LTα-TNF receptor 1 complexes, we used all-atom molecular dynamics simulations to investigate the stabilizing interactions between these ligand-receptor pairs. Additionally, we simulated both complexes with destabilizing point mutations. The simulation results yield insight into published experimental data as well as the underlying mechanism of high affinity ligand-receptor binding.