Homology modeling of mouse NLRP3 NACHT protein domain and molecular dynamics simulation of its ATP binding properties

Gout is an extremely painful form of inflammatory arthritis, caused by the formation of monosodium urate (MSU) crystals in the joints. MSU crystals are one of the triggers for the activation of nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome (NACHT, LRR and PYD domains-containing protein), which in turn induces caspase-1 activation and a nonspecific immune responses that cause inflammation. Further structural studies and ligand designs are needed to block the interaction of NLRP3 with MSU or allow the interaction without activating caspase-1. This would facilitate the screening of new drugs for the treatment of gout. Using computational methods for homology modeling and molecular dynamics simulations, the structural model of mouse NLRP3 protein with its domains, three potential structural models were consistently constructed and tested to find the most stable structural model. Adenosine triphosphate (ATP) — an activator of NACHT (the central domain of mouse NLRP3 protein) — was docked and simulated. Ligand effects to activate as well as limit this protein were analyzed. This study provides insights to deeper understanding about gout development pathway via the NLRP3 protein.