Investigating The Molecular Mechanism Of Halogenated Organic Contaminants To Inhibit The Thyroid Hormine Sulfotransferase SULT1A1

Thyroid hormones?THs?is critical to the normal development and differentiation of all cells of organisms,and the disorder of the thyroid function can cause the abnormal development of the central nervous system,the lung system,the cardiovascular system and other organs.It has been reported that the halogenated organic pollutants?HOCs?and its hydroxylation metabolites in the environment have thyroid interference effect.Inhibiting biological enzymes by HOCs involved in metabolism of THs,such as deiodinase?DIs?and sulfonyltransferase?SULTs?,is an important way to interfere with thyroid hormone effect by HOCs and its metabolites,while the mechanism of HOCs to inhibit the related enzymes is still unclear.With the continuous improvement and development of computer technology,theoretical computational chemistry has been widely used in the fields of biological enzyme-catalyzed organic metabolism,migration and transformation of organic pollutants etc.It plays an important role in revealing the toxic mechanism of pollutants and the molecular mechanism of environmental behavior.In this study,different theoretical calculation methods were used,HOCs,such as hydroxyl polybrominated diphenyl ethers?OH-PBDEs?,hydroxylated polychlorinates?OH-PCBs?,triclosan,and2,4,6-trihalogenated phenol and bisphenol A?BPA?were selected as the research objects to explore the molecular mechanism on inhibition of THs SULT1A1.Then the reaction path of sulfonation catalyzed by SULT1A1 enzyme,the transition state and the structure characteristics of intermediates in the reaction process were determined,and the corresponding energies were obtained.In addition,the position of substitution of hydroxyl?-OH?,the number of bromine atoms,and the influence of HOCs by different halogen atoms substituted were discussed,which may provides datas basis for other studies.The research contents and main conclusions of this paper are as follows:?1?Based on the molecular docking,dynamic simulation and QM/MM method,here17 OH-PBDEs with lower brominated monohydroxy substituted were selected,to investigate the interaction between OH-PBDEs and thyroid sulfonyltransferase macromolecules.The binding conformation and non-bond interaction between HO-PBDEs and SULT1A1 were revealed,and then the mechanism of endocrine disrupting activity of HO-PBDEs was explored at the molecular level.The molecular docking results demonstrated that most of selected OH-PBDEs form hydrogen bonds with both residues Lys106 and His108 of SULT1A1,and the neutral OH-PBDEs showed comparable binding energies with their anionic counterparts.The two-step reaction path between OH-PBDEs and SULT1A1,including proton transfer and sulfonation reaction,was first proposed by QM/MM calculation,which provides a new way to explore the enzyme inhibition mechanism of OH-PBDEs.This reaction mechanism is important for enzyme inhibition of OH-PBDEs containing three or less Br atoms,especially OH-PBDEs with para hydroxyl groups.The other OH-PBDEs likely only form ternary dead-end complex with SULT1A1to inhibit enzyme activity.In addition,the calculated results showed that the relative position of OH and ether bond has an important effect on sulfonation reaction,and the order of sulfonation product formation is as follows:ortho-OH BDE>meta-OH BDE>para-OH BDE.Furthermore the steric hindrance effect of bromine atoms in OH-PBDEs will also affect the occurrence of sulfonation reaction.?2?Based on the density functional theory?DFT?,a simplified model including HOCs compounds and PAPS cofactor is further constructed to improve the computational efficiency.In this work,the chemical set contains 31 HOCs,including OH-PBDEs,OH-PCBs,triclosan,fluorinated,chlorinated,brominated,and iodinated analogues of2,4,6-trihalogenated phenol and bisphenol A were selected to study the inhibition effect on SULT1A1.For OH-PBDEs,ortho-OH BDE contributes greatly to the sulfation of HOCs,and the more bromine atoms,the greater the steric hindrance effect,and not conducive to the process of sulfation.As far as OH-PCBs are concerned,we found that sulfation of BDE3 substituted by para-OH is more likely to occur.In addition,for 2,4,6-trihalogenated phenol,the order of sulfation activity is as follows:TIP?TCP>TBP>TFP,and for halogen substituted bisphenol A derivatives,the activity order is TCBPA>TBBPA>TIBPA>BPAAF.In this study,we constructed the corresponding chemical reaction model to analyze the sulfation process of HOCs catalyzed by SULT1A1,and explained the mechanism of HOCs inhibiting the activity of sulfotransferase at the molecular level.It can provide a new level of insight into the thyroid interference effect of this kind of organic pollutants.?3?Developing predictive quantitative structural activity relationship?QSAR?model for SULT1A1 inhibition of halogenated phenolic chemicals by molecular electronic and energy parameters,and analyzing the molecular structural properties or interactions that govern their SULT1A1 inhibition.Three molecular descriptors were selected in this model:molecular volume?V?,the most positive net atomic charges of hydrogen atoms?qH⁺?and the energy of the second lowest unoccupied molecular orbital(E_LUMO2).The result indicated that steric hindrance,hydrogen bond,and electrophilic reactivity play important roles in inhibiting SULT1A1 activity.The QSPR model had good prediction quality and predictive robustness?r²=0.84,q²=0.84,rms=0.35,me=0.29,training set;r²=0.87,q²=0.87,rms=0.34,me=0.26,test set?.