Experimental and computational insights on the recognition mechanism between the estrogen receptor α with bisphenol compounds.

Certain bisphenols (BPs) have been regarded as endocrine-disrupting chemicals due to their structural similarities to bisphenol A (BPA), a well-known weak estrogenic chemical. However, very limited data are currently available on the relationship between estrogenic activity and the structure of BP analogs. Therefore, we systematically investigated the estrogenic potency of 14 selected BP analogs with typical structures using experimental and computational methods. Most of the tested BP analogs exhibited weak estrogenic activities in both cell proliferation and MVLN assays with the exception of TBBPA, TCBPA and TBBPS. Molecular modeling techniques have been performed to investigate the dynamic structural characteristics of recognition processes between BPs and estrogen receptor α (ERα) at the atomic level. Thr347 was identified as the key residue responsible for the recognition of TBBPA, TCBPA and TBBPS by means of induced-fit H-bonding interactions in the binding pocket of ERα, whereas other BPs, in turn, rely on the alternative formation of H-bonds with His524. Subsequent allosteric modulation interferes significantly with the stability of helix 12 that is crucial for the transcriptional activity of ERα. These structural perturbations that are induced by the three compounds were further confirmed to reduce the recruitment potency of co-activators more than other BPs based on calculations of binding free energies, which is in line with observed experimental transcriptional activities. Our findings may help to elucidate the estrogenic potency of BPs with different molecular structures.