Abstract

The NLR family caspase recruitment domain-containing protein 4 (NLRC4) inflammasome regulates the inflammatory response. Upregulation of NLRC4 inflammasome has been associated with bacterial infections, cancers, and autoinflammatory disorders (AIDs). The Q657L mutation in the NLRC4 causes AID. However, the structural change upon Q657L mutation at the atomic level has not been clearly understood. In this study, we employed in silico predictions along with molecular dynamics (MD) simulations of the homology modelled human wild-type and mutant NLRC4 structures in the resting and activated state to investigate the impact of Q657L mutation on the structural and dynamic changes of NLRC4 protein. The Q657L mutation was predicted to be deleterious by various in silico prediction tools. The MD simulation results demonstrated that the mutation increased the stability of the compactly folded structure and decreased flexibility in the resting state. In the activated state, the stably folded mutant structure had increased solvent accessible surface area, intermolecular hydrogen bonds and binding pocket volume. In addition, the principal component analysis showed that the mutant structures had reduced dynamics in both states. These findings provide insights into structural and dynamic changes of NLRC4 protein due to Q657L mutation at the atomic level.