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

Abstract

Background: In 2017, the World Health Organization announced a list of the most dangerous superbugs. Among them is Pseudomonas aeruginosa, an opportunistic human pathogen with high levels of resistance to antibiotics that is listed as one of the ‘ESKAPE’ pathogens, which are the leading cause of nosocomial infections. A major issue is that it mostly affects vulnerable patients such as those suffering from AIDS, cystic fibrosis, cancer and severe burns. P. aeruginosa creates and inhabits surface-associated biofilms which increase resistance to antibiotics and host immune responses and contribute to the ineffectiveness of current antibacterial treatments. It is therefore imperative to find new antibacterial treatment strategies against P. aeruginosa. The LasR protein is a major transcriptional activator of P. aeruginosa and plays a pivotal role in biofilm formation and the activation of many virulence genes, although detailed characteristics of the LasR protein are not currently known. In the present study, we aimed to analyse the molecular properties of the LasR protein as well as its interactions with the signalling molecule N-3-oxododecanoyl homoserine lactone (3OC12-HSL). Methods: We used a combination of molecular docking, molecular dynamics (MD) simulations and machine learning techniques to study the interaction of the LasR protein with the 3OC12-HSL ligand. We assessed conformational changes occurring upon their interaction and analysed the molecular details of their binding. Results: A new possible interaction site for 3OC12-HSL and LasR was found, involving conserved residues from the ligand binding domain (LBD), beta turns in the short linker region (SLR) and the DNA-binding domain (DBD). This interaction is referred to as the LBD-SLR-DBD bridge or ‘the bridge’ interaction. Conclusions: This study may enable future experimental studies to detect the interaction of signalling molecules with “the bridge” of the LasR protein and suggests a potential new interaction site to assist antibacterial drug design.