Disrupting quorum sensing by exploring conformational dynamics and active site flexibility of LasR protein in Pseudomonas aeruginosa

Abstract

Quorum sensing in Pseudomonas aeruginosa, regulated by the LasR protein, controls bacterial virulence and biofilm formation. Targeting this system offers a promising strategy to combat infections. This study investigates the binding and conformational dynamics of LasR with its native ligand, N-3-oxo-dodecanoyl-L-homoserine lactone (AHL), and a natural product compound, ClaO, using molecular docking, molecular dynamics simulations, and binding free energy calculations. Docking validation confirmed AHL’s accurate re-docking (binding energy: − 8.3 kcal/mol, RMSD: 1.199 Å). ClaO exhibited a stronger binding affinity (− 8.9 kcal/mol), suggesting favorable interactions with LasR. Both ligands formed key hydrophobic and hydrophilic contacts with residues such as TRP60, TYR93, SER129, and ASP73. Molecular dynamics simulations revealed that AHL stabilized the LasR structure, while ClaO induced increased flexibility, indicating different binding mechanisms. Binding free energy analysis showed that ClaO had stronger van der Waals (− 187.6 kJ/mol) and electrostatic interactions (− 139.4 kJ/mol) than AHL (− 182.9 kJ/mol, − 131.8 kJ/mol). However, ClaO’s higher polar desolvation energy (287.2 kJ/mol) reduced its binding efficiency. AHL had a slightly more favorable binding free energy (− 76.3 kJ/mol) compared to ClaO (− 72.6 kJ/mol), suggesting a more stable interaction. These findings highlight the differential effects of AHL and ClaO on LasR stability and flexibility. While ClaO engages in stronger interactions, its desolvation penalty offsets its binding advantage. This study provides molecular insights into quorum sensing inhibition and supports the development of novel LasR-targeting therapeutics. Clinical trial number: Not applicable.