Objective::The NLRP3 inflammasome mediates a range of inflammatory responses
that are associated with an increasing number of pathological mechanisms. Over-activation of
NLRP3 can exacerbate many diseases. However, NLRP3 antagonists have significant therapeutic
potential. Moreover, NLRP3 plays an important role in limiting the growth and spread of
some tumors, and NLRP3 agonists also have clinical value. MCC950 and BMS986299 are an
antagonist and agonist of NLRP3, respectively. In light of the important clinical applications of
NLRP3, especially for NLRP3 inhibitors, a computational method was used to investigate the
interaction modes of MCC950 and BMS986299 with NLRP3 in order to design and develop
more potent NLRP3 regulators.Methods::In this study, the conformational behaviors of NLRP3 bound to the antagonist
MCC950 in an inactive state and the agonist BMS986299 in an active state were investigated
using 200 ns equilibrium all-atom molecular dynamics (MD) simulations, and then the analyses
of the MD trajectories (RMSD, Rg, RMSF, SASA, PCA, and DCCM) were carried out to explore
the mechanism of the antagonist and agonist on NLRP3 in the two different states.Results::The RMSD, RMSF, Rg, SASA, and PCA analyses indicated that NLRP3 was more
dispersive and less energetically stable in the active state than in the inactive state and that
MCC950 significantly reduced the fluctuations of the interactive residues while BMS986299
did not. The antagonist MCC950 interacted with residues mainly in the NBD, HD1, WHD, and
HD2 domains of NLRP3, whereas the agonist BMS986299 mainly in the NBD and WHD of
NLRP3. Additionally, both compounds did not interact with residues located in the FISNA domain.
The conformation of the FISNA domain appeared to change significantly when NLRP3
was translated from an inactive state to an active state.Conclusion::The antagonist may interact with residues mainly in the NBD, HD1, WHD, and
HD2 domains, and the agonist may interact in the NBD and WHD domains. Our study provided
new insights into the development of NLRP3 regulators.