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

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.