Binding affinity between AhR and exogenous/endogenous ligands: molecular simulations and biological experiment

Aryl hydrocarbon receptor (AhR) plays critical roles in cell differentiation, and its mechanism is controlled by exogenous and endogenous ligands. However, structures of AhR and its complex with ligand have not been determined by experimental structural biology. We here obtain stable structures of the complexes with rat AhR (rAhR) and some ligands in water by molecular simulations based on homology modelling, protein–ligand docking, classical molecular mechanics optimisation and ab initio fragment molecular orbital (FMO) calculations. In addition, the binding affinities and the specific interactions between rAhR and the ligands are investigated by ab initio FMO calculations and biological experiments. The experiments reveal the dependence of the rAhR-mediated transcriptional activation on the ligand binding. On the other hand, the results of FMO calculations elucidate that the exogenous ligands interact with many residues of rAhR, while the endogenous ligands interact specifically with a few residues, and...