Look What You Made Me Do: Discerning Feature for Classification of Endocrine-Disrupting Chemical Binding to Steroid Hormone Receptors

Exposure to metabolism-disrupting chemicals, which are a specific type of endocrine-disrupting chemical (EDC), is linked to metabolic problems such as dyslipidemia, insulin resistance, and hepatic steatosis. Steroid hormone receptors (SHRs) within the nuclear receptor superfamily are well-known targets for EDCs in reproductive tissues and, to a lesser extent, in liver. In this study, we investigated how five well-established SHR ligands and eight EDCs including pesticides, plasticizers, pharmaceuticals, flame retardants, industrial chemicals, and their metabolites affect estrogen (ERα in reproductive tissues) and glucocorticoid (GR in liver) receptors. We investigated the utility of structural molecular modeling to classify EDC binding to ERα and GR. To this end, we modeled a set of EDC binding to ER and GR using unbiased all-atom long-time scale molecular dynamics (MD) simulations and compared them against known established SHR agonists and antagonists. We systematically evaluated MD-derived variables such as protein–ligand interactions and binding energy, folding secondary structure elements, distances, and angles as relevant parameters. Our findings suggest that the well-established H12 folding and conformational angles can be discerning features for binding of EDCs to SHRs. Although SHR activation often involves changes in H12 folding and geometry, GR displayed less flexibility in this region, suggesting that protein–ligand interaction and binding energy are more relevant for its classification. We show that MD simulations combined with experimental assays can be a useful tool for studying novel EDCs by providing relevant structural features for their classification.代谢干扰物作为一类特殊的内分泌干扰物（EDC），其暴露风险与血脂异常、胰岛素抵抗、肝脂肪变性等代谢紊乱存在显著关联。隶属于核受体超家族的类固醇激素受体（SHRs）是生殖组织中内分泌干扰物的经典靶点，在肝脏中的此类作用则相对较弱。本研究针对5种经典类固醇激素受体配体，以及涵盖农药、塑化剂、药物、阻燃剂、工业化学品及其代谢产物在内的8种内分泌干扰物，探究其对生殖组织雌激素受体α（ERα）与肝脏糖皮质激素受体（GR）的调控作用。同时，本研究还评估了结构分子建模用于分类内分泌干扰物与ERα、GR结合模式的应用潜力。为此，我们通过无偏全原子长时间尺度分子动力学（MD）模拟，构建了一系列与ER、GR结合的内分泌干扰物模型，并与已验证的类固醇激素受体激动剂、拮抗剂进行对照分析。我们系统评估了源自分子动力学模拟的多项关键参数，包括蛋白质-配体相互作用、结合能、折叠二级结构元件、距离与角度等。研究结果显示，经典的H12折叠与构象角度可作为区分内分泌干扰物与类固醇激素受体结合特异性的特征指标。尽管类固醇激素受体的激活通常伴随H12折叠与构象的改变，但糖皮质激素受体在该区域的灵活性相对更低，这提示蛋白质-配体相互作用与结合能对其分类更为关键。本研究证实，结合实验检测的分子动力学模拟可作为研究新型内分泌干扰物的有效工具，能够为其分类提供关键结构特征。