Pleotropic potential of quorum sensing mediated N-acyl homoserine lactones (AHLs) at the LasR and RhlR receptors of Pseudomonas aeruginosa

Pseudomonas aeruginosa is an opportunistic pathogen, having complicated quorum sensing (QS) system utilizing multiple signals and receptors to coordinate virulence and pathogenicity. N -acyl-homoserine-lactones (AHLs) are the most common autoinducers responsible for regulation of QS mediated virulence gene expression. There are two interrelated QS systems in P. aeruginosa namely, LasI/R and RhlI/R, which are regulated by 3-oxo-C 12 -HSL and C 4 -HSL respectively and well explored in host-associated pathogenesis. The LasR and RhlR binding specificity to cognate or non-cognate HSLs influences the QS mediated responses. In the current study, using computational approaches we aimed to consolidate the interaction of different types of HSLs which are produced during P. aeruginosa infection with LasR and RhlR receptors. To explore the binding affinity, fourteen different AHLs were subjected for molecular docking analysis with LasR and RhlR receptors. The RhlR was modelled using MMseqs2 in ColabFold: Alpha fold 2. Further, to validate the stability and interaction mechanism, molecular dynamic simulations was performed with the top docked six HSLs for 100 ns. In docking results, apart from 3-oxo-C 12 -HSL and C 4 -HSL, other HSLs such as C 16 -HSL and C 6 -HSL showed better binding affinity towards LasR and RhlR respectively. Further validation by molecular dynamic simulations showed that 3-oxo-C 10 -HSL has a stable complex formation with LasR and 3-oxo-C 6 -HSL with RhlR. Our comprehensive Insilco study results may provide promising targets for development of anti-QS drugs against Las/Rhl QS systems.