通过分子对接、分子动力学模拟和结合自由能计算,了解羟基化和硫酸化多溴联苯醚与转甲状腺素的微观结合机制

IF 3.743 Q2 Biochemistry, Genetics and Molecular Biology
Huiming Cao, Yuzhen Sun, Ling Wang, Chunyan Zhao, Jianjie Fu and Aiqian Zhang
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引用次数: 14

摘要

多溴联苯醚(PBDEs)是一种典型的持久性环境污染物,具有破坏人体内甲状腺稳态等毒理学效应。多溴二苯醚羟基化代谢物(OH-PBDEs)与转甲状腺素(TTR)的高结合亲和力被认为是其通过竞争性甲状腺激素(T4)转运蛋白结合通过血脑屏障的非凡能力的一个主要原因。最近的研究表明,硫酸多溴二苯醚可以在人肝细胞质中作为ii相代谢产物形成。然而,关于硫酸多溴二苯醚的TTR结合势的实验确定数据仍然不可用。因此,本研究采用分子对接和分子动力学(MD)模拟,在原子水平上探讨TTR与羟基化和硫酸化多溴二苯醚相互作用的分子基础。利用LeDock的对接分数构建基于结构的预测模型。计算结果表明,与相应的OH-PBDEs相比,硫酸盐PBDEs对TTR具有更强的亲和力。基于MD模拟的进一步结构特征分析表明,结合PBDE代谢物后,TTR的稳定性增强,四聚体蛋白结构的解离率可能降低。随后的结合自由能计算表明,范德华相互作用是多溴二苯醚代谢物在TTR的T4位点结合的主要力量。通过残基能量分解和计算丙氨酸扫描诱变方法,鉴定出Ser117/Ser117’和Lys15/Lys15’是决定-OSO3 ?通过形成氢键或静电相互作用,分别形成硫化多溴二苯醚基团。总的来说,对接计算与MD模拟的结合为多溴二苯醚代谢物提供了理论上的毒理学评估,深入了解了TTR对这些化合物的识别机制,从而更全面地了解了多溴二苯醚的甲状腺相关毒性作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Understanding the microscopic binding mechanism of hydroxylated and sulfated polybrominated diphenyl ethers with transthyretin by molecular docking, molecular dynamics simulations and binding free energy calculations†

Understanding the microscopic binding mechanism of hydroxylated and sulfated polybrominated diphenyl ethers with transthyretin by molecular docking, molecular dynamics simulations and binding free energy calculations†

Polybrominated diphenyl ethers (PBDEs), one typical type of persistent environmental contaminant, have toxicological effects such as disrupting thyroid homeostasis in the human body. The high binding affinities of hydroxylated metabolites of PBDEs (OH-PBDEs) with transthyretin (TTR) were considered to be one major reason for their extraordinary capacity of passing through the blood–brain barrier via competitive thyroid hormone (T4) transport protein binding. Recent findings showed that sulfated PBDEs can be formed in human liver cytosol as phase-II metabolites. However, experimentally determined data for the TTR binding potential of the sulfated PBDEs are still not available. Therefore, molecular docking and molecular dynamics (MD) simulations were employed in the present study to probe the molecular basis of TTR interacting with hydroxylated and sulfated PBDEs at the atomic level. The docking scores of LeDock were used to construct the structure-based predictive model. The calculated results showed that the sulfated PBDEs have stronger affinity for TTR than the corresponding OH-PBDEs. Further analysis of structural characteristics based on MD simulations indicated that upon the binding of PBDE metabolites, the stability of TTR was enhanced and the dissociation rate of the tetrameric protein structure was potentially decreased. Subsequent binding free energy calculations implied that van der Waals interactions are the dominant forces for the binding of these metabolites of PBDEs at the T4 site of TTR. The residues Ser117/Ser117′ and Lys15/Lys15′ were identified, by both residue energy decomposition and computational alanine-scanning mutagenesis methods, as key residues which play an important role in determining the binding orientations of the –OSO3? group of sulfated PBDEs by formation of either hydrogen bonds or electrostatic interactions, respectively. In general, the combination of docking calculations with MD simulations provided a theoretically toxicological assessment for the metabolites of PBDEs, deep insight into the recognition mechanism of TTR for these compounds, and thus more comprehensive understanding of the thyroid-related toxic effects of PBDEs as well.

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来源期刊
Molecular BioSystems
Molecular BioSystems 生物-生化与分子生物学
CiteScore
2.94
自引率
0.00%
发文量
0
审稿时长
2.6 months
期刊介绍: Molecular Omics publishes molecular level experimental and bioinformatics research in the -omics sciences, including genomics, proteomics, transcriptomics and metabolomics. We will also welcome multidisciplinary papers presenting studies combining different types of omics, or the interface of omics and other fields such as systems biology or chemical biology.
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