Comparative study on the binding of several per- and Polyfluoroalkyl Substances (PFAS) to the G Protein-coupled Estrogen Receptor (GPER) using molecular docking technology

Per- and polyfluoroalkyl substances (PFAS) constitute a class of persistent organic pollutants with estrogen-disrupting effects. The molecular mechanism underlying their mediation of rapid non-genomic signaling pathways through the G protein-coupled estrogen receptor (GPER) remains incompletely elucidated. This study selected three representative PFASperfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorobutyric acid (PFBA)based on the following criteria: PFOS and PFOA are the most ubiquitous traditional long-chain PFAS in the environment, characterized by potent bioaccumulative potential, while PFBA, as a representative short-chain PFAS, is widely used as a substitute for long-chain PFAS. Molecular docking techniques were employed to simulate and compare the interactions between these three PFAS and the GPER-specific agonist G1 with the receptor. The results indicated the following binding affinity order for ligands with GPER: G1 (-7.26 kcal/mol) > PFOS (-6.09 kcal/mol) > PFOA (-5.48 kcal/mol) > PFBA (-4.45 kcal/mol). Binding mode analysis revealed that PFOS exhibits the highest binding affinity due to its sulfonate group forming salt bridges and multiple halogen bonds. In contrast, PFOA and PFBA primarily engage in hydrophobic interactions and halogen bonds, with their binding affinity diminishing as the perfluorinated carbon chain length decreases.