Interaction of N-3-oxododecanoyl homoserine lactone with transcriptional regulator LasR of Pseudomonas aeruginosa: Insights from molecular docking and dynamics simulations

Background In 2017 World Health Organization announced the list of the most dangerous superbugs and among them is Pseudomonas aeruginosa, which is an antibiotic resistant opportunistic human pathogen as well as one of the ‘SKAPE’ pathogens. The central problem is that it affects patients suffering from AIDS, cystic fibrosis, cancer, burn victims etc. P. aeruginosa creates and inhabits surface-associated biofilms. Biofilms increase resistance to antibiotics and host immune responses, because of those current treatments are not effective. It is imperative to find new antibacterial treatment strategies against P. aeruginosa, but detailed molecular properties of the LasR protein are not clearly known to date. In the present study, we tried to analyse the molecular properties of the LasR protein as well as the mode of its interactions with autoinducer (AI) the N-3-oxododecanoyl homoserine lactone (3-0-C12-HSL).

Results We performed docking and molecular dynamics (MD) simulations of the LasR protein of P. aeruginosa with the 3-0-C12-HSL ligand. We assessed the conformational changes of the interaction and analysed the molecular details of the binding of the 3-0-C12-HSL with LasR. A new interaction site of the 3-0-C12-HSL with LasR protein was found, which involves interaction with conservative residues from ligand binding domain (LBD), beta turns in the short linker region (SLR) and DNA binding domain (DBD). It will be referenced as the LBD-SLR-DBD bridge interaction or “the bridge”. We have also performed LasR monomer protein docking and found a new form of dimerization.

Conclusions This study may offer new insights for future experimental studies to detect the interaction of the autoinducer with “the bridge” of LasR protein and a new interaction site for drug design.