Arnold Abakah

Ghana

Conformational Dynamics and Active Site Flexibility in the Pseudomonas aeruginosa LasR Protein: Inhibiting the Quorum Sensing Receptor

Prince Manu1,3, Arnold Abakah2, Paa Kwesi Anfu2, Priscilla Osei-Poku2,3, Alexander Kwarteng2,3*

1. Department of Chemistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
2. Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
3. Kumasi Centre for Collaborative Research in Tropical Medicine, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

Abstract

Background

Pseudomonas aeruginosa employs quorum sensing (QS) to regulate virulence factors, including biofilm formation. Disrupting QS offers a promising alternative to traditional antibiotics. This study investigates the conformational dynamics and active site flexibility of the LasR protein, a key QS receptor in P. aeruginosa, upon binding with a marine-derived compound, cladosporiumin O. The findings provide insights into the potential of this compound as a novel inhibitor of P. aeruginosa QS.

Methods

This study employed computational methods to investigate the interaction between potential inhibitors and the LasR receptor from P. aeruginosa. Protein preparation involved structure retrieval, energy minimization with the AMBERff4SB force field, and ligand preparation using DFT. Molecular docking was performed using global and precision approaches using AutoDock Vina. Molecular dynamics simulations were conducted to evaluate the stability of the protein-ligand complexes using GROMACS V.2018.6 on the Lengau cluster.

Results

Molecular dynamics simulations revealed distinct conformational behaviors for the LasR receptor bound to different ligands. The native ligand, OHN, exhibited stable binding and minimal structural fluctuations with an RMSD of 1.199 Å over the 200 ns simulation, while the inhibitor ClaO showed greater flexibility and conformational changes with an RMSD that fluctuated between 0.6 and 0.8 nm. The RMSD values for both remained below 2 nm, indicating stable binding at the active site.
The conformational dynamics of the LasR receptor was significantly influenced by ligand binding. AHL, stabilized the protein structure, limiting its conformational flexibility. In contrast, ClaO, allowed for greater flexibility, potentially indicating a different binding mode or interaction with the protein. These findings suggest that targeting the conformational dynamics of the LasR receptor could be a promising strategy for developing novel inhibitors to disrupt quorum sensing in P. aeruginosa.

Conclusions

This study highlights the impact of ligand binding on the conformational dynamics of the LasR protein. AHL stabilizes the protein structure, while ClaO allows for greater flexibility. These findings offer valuable insights for designing inhibitors that target the LasR receptor to disrupt quorum sensing in P. aeruginosa.