Binding characteristics of hydroxylated polybrominated diphenyl ether with thyroid protein and its potential toxicity

Abstract

As a derivative of polybrominated diphenyl ether (PBDEs), hydroxy polybrominated diphenyl ether (OH-PBDEs) is a kind of persistent organic pollutants with endocrine disrupting effect. Due to OH-PBDEs and T4 are similar in structure, they are likely to compete with T4 for binding to thyroid protein. Therefore, it is necessary to study the interaction mechanism between OH-PBDEs and thyroid protein. The interaction mechanism of 6-OH-BDE-85 with transthyretin (TTR) and thyroxine (T4)-binding globulin (TBG) were compared by computational simulation and multi-spectroscopic methods, and the binding free energies were calculated by the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method. The results of molecular docking showed that 6-OH-BDE-85 was wrapped in the cavity by TTR hydrophobic residues and formed hydrogen bonds with LYS15 residues. 6-OH-BDE-85 and TBG combine mainly through cation-π interaction and hydrophobic interaction. Molecular dynamic simulations indicated that the hydrophobic area and hydrophobic effect of TTR and TBG increased after binding to 6-OH-BDE-85, which made the composite more stable than that of the free protein. According to the energy decomposition analysis, the amino acid residues located near the binding sites of TTR and TBG had higher binding free energy, which further confirmed that small molecules could enter the active cavity. The observed binding constant showed that 6-OH-BDE-85 had a stronger binding ability with TBG than with TTR. Infrared spectroscopy revealed that the presence of 6-OH-BDE-85 induced changes in the secondary structures of TTR and TBG.