Molecular interactions between halogenated bisphenol compounds and GPER: Spectroscopic, molecular simulation, and DFT calculations

Halogenated bisphenols (HBPs) are widely detected environmental contaminants present in water systems, soil, and biota. The incorporation of halogen substituents (Cl, Br) enhances their environmental persistence and potential toxicological effects. Understanding the cellular responses to HBPs exposure in living organisms is therefore essential for evaluating their human health implications. This study comprehensively characterizes the binding patterns and interaction mechanisms of HBPs with the G protein-coupled estrogen receptor (GPER) through an integrated approach combining multispectral analysis, molecular dynamics (MD) simulations, and quantum chemical calculations. Computational results reveal that hydrogen bonding and van der Waals interactions primarily mediate GPER-HBPs binding, with binding affinity modulated by both halogen atom count and the chemical nature of bridging groups between benzene rings. Binding of HBPs induces significant structural alterations in GPER, including conformational rearrangements, molecular compaction, enhanced hydrophobicity, and modifications to the microenvironment and secondary structure. Fourier-transform infrared (FT-IR) and three-dimensional fluorescence spectroscopy confirm secondary structure reorganization, particularly evidenced by reduced β-sheet content. Stern-Volmer analysis establishes static quenching as the dominant mechanism, correlated with specific HBPs binding modes and sites. Density functional theory (DFT) calculations identify hydrogen bonds, halogen bonds, and electrostatic interactions as key driving forces, supplemented by weaker intermolecular contributions. These insights advance the assessment of health risks associated with HBPs-type environmental pollutants.