Atomic Insights into Distinct Hormonal Activities of Bisphenol A Analogues toward PPARγ and ERα Receptors

Bisphenol A analogues (BPAs) belong to a wide variety of large volume chemicals with diverse applications yet emerging environmental concerns. Limited experimental data have demonstrated that BPAs with different halogenation patterns distinctly affect the agonistic activities toward proliferator-activated receptor (PPAR)gamma and estrogen receptors (ER)a. Understanding the modes of action of BPAs toward different receptors is essential, however, the underlying molecular mechanism is still poorly understood. Here we probed the molecular recognition process of halogenated BPAs including TB13PA, TCBPA, BPAF, BPC, triBBPA, diBBPA, and monoBBPA toward PPAR gamma and ER alpha by molecular modeling, especially the impact of different halogen patterns. Increasing bromination at phenolic rings of BPAs was found highly correlated with electrostatic interactions (R-2 = 0.978 and 0.865 toward PPAR gamma and ER alpha, respectively) and van der Waals interactions (R-2 = 0.995 and 0.994 toward PPAR gamma and ERa, respectively). More halogenated phenolic rings at 3,5 positions of 13PA.s increase the shielding of the hormonally active phenolic OH and markedly decrease electrostatic interactions favorable for agonistic activities toward PPARy, but unfavorable for agonistic activities toward ERa. The halogenation at the phenolic rings of BPAs exerts more impact on molecular electrostatic potential distribution than halogenation at the bridging alkyl moiety. Different halogenations further alter hydrogen bond interactions of BPAs and induce conformational changes of PPARy ligand binding domain (LBD) and ERa LBD, specifically affecting the stabilization of helix H12 attributable to the different agonistic activities. Our results indicate that structural variations in halogenation patterns result in different interactions of BPAs with PPARy LBD and ERa LBD, potentially causing distinct agonistic/antagonistic toxic effects. The various halogenation patterns should be fully considered for the design of future environmentally benign chemicals with reduced toxicities and desired properties.