Insight into the Binding Interaction between PEDCs and hERRγ Utilizing Molecular Docking and Molecular Dynamics Simulations

TL;DR

This study explores how certain environmental chemicals interact with a human receptor at the molecular level, revealing key binding patterns and energy contributions.

Contribution

The study identifies specific amino acid residues and binding energy contributors in the interaction between PEDCs and hERRγ, with a novel focus on methoxide groups reducing binding energy.

Findings

Residues Leu271, Leu309, Leu345, and Phe435 are crucial for PEDC binding to hERRγ.

CH-π, π-π, and hydrogen bonds are the main contributors to the binding energy of PEDCs with hERRγ.

Methoxide groups in BP(2,2)(Me) reduce the binding energy of PEDCs with hERRγ.

Abstract

Phenolic environmental endocrine-disrupting chemicals (PEDCs) are persistent EDCs that are widely found in food packaging materials and environmental media and seriously threaten human health and ecological security. Human estrogen-related receptor γ (hERRγ) has been proposed as a mediator for the low-dose effects of many environmental PEDCs; however, the atomic-level descriptions of dynamical structural features and interactions of hERRγ and PEDCs are still unclarified. Herein, how three PEDCs, 4-(1-methylpropyl)phenol (4-sec-butylphenol), 5,6,7,8-tetrahydro-2-naphthol (tetrahydro-2-napthol), and 2,2-bis(4-hydroxy-3,5-dimethoxyphenyl)propane (BP(2,2)(Me)), interact with hERRγ to produce its estrogenic disruption effects was studied. Molecular docking and multiple molecular dynamics (MD) simulations were first conducted to distinguish the detailed interaction pattern of hERRγ with PEDCs. These binding structures revealed that residues around Leu271, Leu309, Leu345, and Phe435 are important when binding with PEDCs. Furthermore, the binding energies of PEDCs with hERRγ were also characterized using the molecular mechanics/Poisson Boltzmann surface area (MM-PBSA) and solvated interaction energy (SIE) methods, and the results showed that the interactions of CH-π, π-π, and hydrogen bonds are the major contributors for hERRγ binding to these three PEDCs. What is striking is that the methoxide groups of BP(2,2)(Me), as hydrophobic groups, can help to reduce the binding energy of PEDCs binding with hERRγ. These results provide important guidance for further understanding the influence of PEDCs on human health problems.

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