Specific interactions between aryl hydrocarbon receptor and dioxin congeners: Ab initio fragment molecular orbital calculations

Optimized structures of the solvated AhR–TCDD and AhR–TrCDD complexes obtained by the AMBER-MM and FMO methods. [Display omitted] ▶ We obtained stable structures of AhR-TCDD and AhR-TrCDD by molecular simulations. ▶ Their electronic properties were investigated by fragment molecular orbital method. ▶ The results indicate that TCDD binds more strongly to rAhR than TrCDD. ▶ His324 and Gln381 of rAhR are important for binding TCDD. ▶ His324 and Ser334 of rAhR are important for binding TrCDD. Aryl hydrocarbon receptor (AhR) is a transcription factor and its function is activated by the binding of halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 1,2,4-trichlorodibenzo-p-dioxin (TrCDD). TCDD is highly toxic to rat, whereas its congener TrCDD shows only a weak effect on gene expression. In order to elucidate the reason of this remarkable difference in the effect of TCDD and TrCDD, we here obtained stable structures of the complexes with rat AhR (rAhR) and TCDD/TrCDD and investigated their electronic properties by using the ab initio fragment molecular orbital (FMO) method. The results indicate that TCDD binds more strongly to rAhR than TrCDD, which is consistent with the experimentally observed toxicity of TCDD and TrCDD. Furthermore, ab initio FMO calculations elucidate that His324 and Gln381 of rAhR are important for binding TCDD, while His324 and Ser334 are important for TrCDD binding.