• A docking-grade bromelain homology model was built (ERRAT: 100; QMEANDisCo: 0. 91). • HADDOCK 2. 4 docking revealed electrostatic-driven binding to the NLRP3 pyrin domain. • Sub-nanomolar affinity was predicted (Kd = 0. 74 nM; ΔG = −12. 5 kcal/mol). • Dual salt bridges (Lys64–Asp60; Lys179–Glu110) anchor the interfacial recognition. • 100 ns MD simulation confirmed complex stability, compactness, and interfacial tightening. Aberrant activation of the NLRP3 inflammasome underpins a broad range of chronic inflammatory conditions, yet pharmacologically safe agents capable of directly intercepting its assembly remain scarce. Bromelain, a multi-enzyme cysteine protease cocktail sourced from Ananas comosus stems, possesses well-characterized immunomodulatory properties; however, whether it can physically occupy the NLRP3 pyrin domain has not been investigated at the atomic level. A stereochemically validated comparative model of stem bromelain (ERRAT quality factor: 100; QMEANDisCo: 0. 91) was subjected to semi-flexible protein–protein docking against the human NLRP3 pyrin domain (PDB: 3QF2) via HADDOCK 2. 4, guided by consensus-derived interfacial residues. Thermodynamic favorability was quantified using PRODIGY and independently cross-checked by MM/GBSA decomposition. Temporal persistence of the predicted pose was evaluated over a 100 ns unrestrained molecular dynamics trajectory (GROMACS/CHARMM36; physiological ionic strength, 0. 15 M NaCl). The preferred docking solution was governed by charge–charge complementarity (ΔGₑlec = −390. 1 kcal/mol; buried interface > 2000 Ų), yielding a predicted dissociation constant in the sub-nanomolar regime (Kd = 0. 74 nM; ΔG = −12. 5 kcal/mol). Nine intermolecular hydrogen bonds and two salt bridges were mapped, with the Lys 64–Asp 60 contact serving as the principal dual-function anchor. The hundred-nanosecond trajectory confirmed conformational equilibrium (RMSD plateau ∼0. 45 nm) ; preserved globular compactness (Rg = 2. 64–2. 71 nm) ; and showed spontaneous interfacial tightening marked by concurrent hydrogen bond accumulation and solvent-accessible surface contraction across the 70–100 ns window. These findings provide a detailed residue-resolution computational demonstration that bromelain occupies the NLRP3 pyrin domain with sub-nanomolar predicted affinity, maintained by a dual electrostatic anchor topology. The results establish bromelain as a structurally rationalized natural candidate for inflammasome-directed anti-inflammatory drug development.
Djelti et al. (Wed,) studied this question.