Predicting Multi-Interfacial Binding Mechanisms of NLRP3 and ASC Pyrin Domains in Inflammasome Activation

NLRP3-PYD inflammasome activates an inflammatory pathway in response to a wide variety of cell damage or infections. Dysregulated NLRP3 inflammatory signaling has many chronic inflammatory and autoimmune disorders. NLRP3 and ASC have a PYD, a superfamily member of the Death Domain, which plays a key role in inflammatory assembly. The ASC interacts with NLRP3 through a homotypic PYD and recruits the procaspase-1 through a homotypic caspase recruitment domain interaction. Here, we used several computational approaches to reveal the interactions of the NLRP3 and ASC PYD domains that lead to the activation of the inflammasome complex. We have characterized ASC and NLRP3-PYD intermolecular interactions by protein–protein docking, and further molecular dynamics (MD) simulations were conducted to evaluate the stability of NLRP3/ASC-PYD complex. Subsequently, we have identified several residues that stabilize the NLRP3/ASC-PYD complex in different faces (i.e., Face-1 to Face-4). The research framework offers new insights into the molecular mechanisms of inflammasome and apoptosis signaling as well as the ease of the drug discovery process.