Are different stoichiometries feasible for complexes between lymphotoxin-alpha and tumor necrosis factor receptor 1?

Applying MM/PBSA methodology to different stoichiometric complexes of human LT-(TNFR1)n=1,2,3 the free energy of binding in these complexes has been estimated by single-trajectory and separate-trajectory methods. Simulation studies rationalized the favorable binding energy in the LT-(TNFR1)1 complex, as evaluated from single-trajectory analysis to be an outcome of the interaction of cysteine-rich domain 4 (CRD4) and the ligand. Elastic network models (ENMs) help to associate the difference in the global fluctuation of the receptors in these complexes. Functionally relevant transformation associated with these complexes reveal the difference in the dynamics of the receptor when free and in complex with LT.MM/PBSA predicts complexes with a ligand-receptor molar ratio of 3:1 and 3:2 to be energetically favorable. The high affinity associated with LT-(TNFR1)1 is due to the interaction between the CRD4 domain with LT. The global dynamics ascertained from ENMs have highlighted the differential dynamics of the receptor in different states.Protein-protein interactions are critical for signaling events within a cell. An investigation on the precise recognition of ligands by their respective receptors is an active field of research, since breakdown of such specific recognition is the root cause of several diseases and infections. One of the rational motives to understand such phenomena is to develop antibodies and small-molecule inhibitors that modulate the outcome of such interactions. One such system that generated immense attention owing to its central role in inflammatory effect, immunological response, but also in several autoimmune diseases and several pathogeneses is the tumor necrosis factor (TNF) [1,2]. Two TNF ligands, namely TNF-α (or TNF) and TNF-β (or lymphotoxin-α, LT) have been extensively studied to methodologically dissect cellular signaling and diseases related to their malfunction [3-6]. It is now well recognized that several cellular responses are directly