Computational insights into the allosteric modulation of E. coli type 1 fimbriae by curcumin: FimH, FimG, FimF, FimA, FimD through docking, dynamics, DFT, MMGBSA analysis.

Curcumin was examined as a possible allosteric modulator of the type 1 fimbrial apparatus in uropathogenic Escherichia coli, a critical virulence mechanism responsible for shear-resistant adhesion, pilus formation, and outer membrane secretion facilitated by FimH, FimG, FimF, FimA, and FimD. An extensive in silico approach was utilized, integrating molecular docking, density functional theory (DFT), 100 ns molecular dynamics (MD) simulations, MM-GBSA binding free energy computations, and post-dynamics analysis such as RMSD, RMSF, secondary structure, PCA, FEL, and DCCM. Docking demonstrated that curcumin associates with interfacial and non-catalytic cavities of all five fimbrial proteins via sustained hydrogen bonding, π-π stacking, and π-cation interactions, exhibiting the greatest affinity for FimF and FimH. DFT characteristics revealed moderate reactivity, elevated electrophilicity, and electron softness, corroborating diverse noncovalent interactions. The MD results validated the establishment of stable protein-ligand complexes, as evidenced by convergent backbone RMSD, decreased residue flexibility in essential areas, and preservation of β-sheet-rich structures. Post-dynamic analysis revealed constrained conformational space, stable low-energy basins, and reduced long-range correlations, collectively indicating diminished catch-bond behaviour, fibrillum plasticity, and usher channel gating. MM-GBSA binding free energies (-74 to -75 kcal/mol) further validated energetically stable but reversible interactions across all targets. The study indicates that curcumin acts as a multi-target allosteric inhibitor, influencing the structural and dynamic networks critical for fimbrial assembly, adhesion, and biofilm persistence, thereby positioning curcumin-like scaffolds as potential candidates for non-bactericidal anti-virulence drug development.