Bridging atomic insights to endocrine hazard: A multiscale simulation and spectroscopic framework for bisphenol-G protein-coupled estrogen receptors interactions

The G protein-coupled estrogen receptor (GPER), widely expressed across human tissues, modulates key physiological processes and associated signaling pathways. Bisphenol A (BPA), a global high-production-volume chemicals, finds extensive use in diverse industrial applications. In this study, we employed an integrated approach of multispectral analysis and molecular simulations to systematically investigate the interaction mechanisms between GPER and bisphenol compounds (BPs), with BPA as a representative. Molecular docking predicted stable binding of BPs within the active pocket of GPER. Solvent-accessible surface area (SASA) analysis revealed an increase in both hydrophobic and hydrophilic surfaces upon BPs binding, indicative of alterations in the protein's microenvironment. Fourier transform infrared (FT-IR) spectroscopy further confirmed that BPs binding induces rearrangement in the secondary structure of GPER. Molecular dynamics simulations revealed an overall structural contraction of GPER upon ligand binding, a conformational change independently corroborated by three-dimensional fluorescence spectroscopy. Energy transfer distance measurements yielded binding distances ranging 2.20 from and 2.80 nm. Notably, the more compact BPF showed the closest proximity, whereas the flexible-chain analog BPE exhibited the farthest, underscoring how substituent structure dictates binding localization. Thermodynamic analysis highlighted the significant roles of hydrogen bonding and hydrophobic interactions. Complementarily, Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) and interaction region indication (IRI) analyses pinpointed van der Waals forces as a major contributor to complex stability. Collectively, our integrated findings decipher the molecular-level interaction mechanism between BPs and GPER. This work provides a theoretical foundation for assessing the endocrine-disrupting potential of bisphenol compounds and aids in the rational design of safer alternatives.