Theoretical Understanding of the Thermodynamics and Interactions in Transcriptional Regulator TtgR-Ligand Binding

The transcriptional regulator TtgR belongs to the TetR family of transcriptional repressors. It depresses the transcription of the TtgABC operon and itself and thus regulates the extrusion of noxious chemicals with efflux pumps in bacterial cells. As the ligand binding domain of TtgR is rather flexible, it can bind with a number of structurally diverse ligands, such as antibiotics, flavonoids and aromatic solvents. In the current work, we perform equilibrium and nonequilibrium alchemical free energy simulation to predict the binding affinities of a series of ligands targeting the TtgR protein and the agreement between the theoretical prediction and the experimental result is observed. End-point methods of MM/PBSA and MM/GBSA are also employed for comparison. We further study the interaction maps and identify important interactions in the protein-ligand binding cases. The current work sheds light on atomic and thermodynamic understanding on the TtgR-ligand interactions.