The role of LasR active site amino acids in the interaction with the Acyl Homoserine Lactones (AHLs) analogues: A computational study

The present work combines molecular docking calculations, 3D-QSAR, molecular dynamics simulations and free binding energy calculations (MM/PBSA and MM/GBSA) in a set of 28 structural analogues of acyl homoserine lactones with Quorum Sensing antagonist activity. The aim of this work is to understand how ligand binds and is affected by the molecular microenvironment in the active site of the LasR receptor for pseudomonas aeruginosa. We also study the stability of the interaction to find key structural characteristics that explain the antagonist activities of this set of ligands. This information is relevant for the rational modification or design of molecules and their identification as powerful LasR modulators. The analysis of molecular docking simulations shows that the 28 analogues have a similar binding mode compared to the native ligand. The carbonyl groups belonging to the lactone ring and the amide group of the acyl chain are oriented towards the amino acids forming hydrogen bond like interactions. The difference in antagonist activity is due to location and orientation of the LasR side chains within the hydrophobic pocket in its binding site. Additionally, we carried out molecular dynamics simulations to understand the conformational changes in the ligand-receptor interaction and the stability of each complex. Results show a direct relationship among the interaction energies of the ligands and the activities as an antagonist of the LasR receptor. (C) 2018 Elsevier Inc. All rights reserved.