Thyroid hormone transporters binding affinity of methoxypoly chlorinated biphenyls: Insights from molecular simulations and fluorescence competitive binding experiment

Abstract

Triiodothyronine (T3) and thyroxine (T4) are essential for regulating cell metabolic rate and promoting the development and differentiation of brain tissue, especially in fetuses and newborns. In particular, it has been proved that MeO-PCBs have high binding to thyroid hormone transporters and can competitively bind to thyroid carrier proteins, thus destroying the transport of the thyroid hormone. Fluorescence competition binding experiments and docking results showed that the binding affinity decreased with the increase in number of chlorine atoms of MeO-PCBs. The interaction mechanism of MeO-PCBs with thyroid transporter (TTR) and thyroid binding globulin (TBG) was compared by computational simulation and the binding free energies were calculated by the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method. Electrostatic potential analysis, Hirshfeld surface analysis and electron density difference maps confirmed the existence of electrostatic interactions. Secondly, noncovalent interaction (NCI) analysis further indicated that the main driving force for the combination of MeO-PCBs to TTR and TBG were electrostatic interaction and van der Waals interaction. The conformational changes of the protein after binding were studied by a molecular dynamic simulation.

Keywords: Binding free energy; Methoxylated polychlorinated biphenyl; Molecular docking; Molecular dynamic simulation.