Molecular Dynamics Study On Interaction Of Estrogen Receptor With Perfluorinated Compounds In Different Species

Perfluorinated compounds(PFCs)have been shown to interfere with the endocrine systems of experimental animals and humans by interacting with estrogen receptor(ER).Considering the possible differential binding preferences and relative binding affinities of perfluorinated compounds(PFCs)to estrogen receptors ?(ER?)from humans and other species,it is necessary to carry on a cross species comparison to effectively assess healthy risk of Perfluorinated compounds(PFCs)to humans.Thus,eight perfluorinated compounds(PFCs)(perfluorooctane sulphonate(PFOS),Perfluorooctanoic Acid(PFOA),Perfluorobutanesulfonic acid(PFBS),Perfluorohexane sulfonate(PFHxS),Perfluorohexane acid(PFHxA),Perfluorobutyric acid(PFBA),Fluorotelomer alcohol(4:2 FTOH and6:2 FTOH))interactions with estrogen receptor ?from human and rat species.The parameters obtained from the experimental results were used to evaluate the difference in the effect of perfluorochemicals on estrogen receptor ?(ER?)in two different species.In the second part of this paper,the serum estrodial levels assay,immunohistochemical staining and western blotting analysis proved that relatively low dose exposure of PFOA and PFOS to female rats did increase the estrogen receptors ?(ER?)expression,which provided evidences that PFOA and PFOS have estrogenic activityin vivo.Based on this,this laid the foundation for subsequent molecular dynamics model predictions.The further fluorescence substitution analysis model demonstrated that eight perfluorinated compounds(PFCs)could bind to estrogen receptor?(ER?)in humans and rats and have a certain binding affinity;the binding affinity ofhuman estrogen receptor ?(ER?)was stronger than that of binding to rat.In the third part of this paper,the ligand binding domain(LBD)of rat estrogen receptor ?was homologously modeled,Perfluorinated compounds(PFCs)are docked to human and rat estrogen receptors?respectively,and all the systems are modeled and analyzed by molecular dynamics simulation.Analysis of the mode of interaction between perfluorinated compounds(PFCs)and estrogen receptor?(ER?)showed that Glu353(H3),Arg394(H5)and His524(H11)as the key amino acids for perfluorinated compounds(PFCs)form hydrogen bonds with the ER?,and perfluorinated compounds(PFCs)interact with human estrogen receptor ER? formed more hydrogen bonds than rat.Studies have shown that the combination of perfluorinated compounds(PFCs)with the estrogen receptor ER? results in a conformational change in the estrogen receptor ER? that affects the information transfer between domains and thus affects the transcriptional activity.The dynamic simulation results showed that the effect of perfluorinated compounds(PFCs)on the ER?was mainly reflected in the change in the conformation of helix 12(H12).The conformational analysis of H12 showed that in the human estrogen receptor ?(ER?)system,the rotation angle of H12 was larger and more stable in the agonist area.QSAR model analysis also demonstrated that H12 movement was a key factor controlling the binding behavior between perfluorochemicals(PFCs)and ER?.At the same time,we also explored the amino acid interaction network of the co-activating region(AF2)and the co-activating polypeptide(TIF2).The results showed that in the human estrogen receptor(ER?)system,the border between the AF2 domain and the TIF2 peptide interacts with each other.The number is always more than the number of interactions in the mouse estrogen receptor(ER?)system,which is mainly reflected in the hydrogen bond network and the van der Waals force network.The calculated results of binding free energy were in accordance with the results of fluorescence substitution experiments.The binding ability of perfluorinated compounds to human estrogen receptor ?(ER?)was stronger than that of rat.In summary,the Perfluorinated compounds(PFCs)were more sensitive to human estrogen receptors ?(ER?)and resulted in more susceptible to adverse effects,which suggested a possible underestimation of endocrine disrupting effects of Perfluorinated compounds(PFCs)in humans.This earlier cross species comparison was the necessary step to identify species-specific binding mechanisms and to accurately evaluate the potential health risks of Perfluorinated compounds(PFCs)in humans.