Detection of persistent organic pollutants binding modes with androgen receptor ligand binding domain by docking and molecular dynamics.
BACKGROUND
Persistent organic pollutants (POPs) are persistent in the environment after release from industrial compounds, combustion productions or pesticides. The exposure of POPs has been related to various reproductive disturbances, such as reduced semen quality, testicular cancer, and imbalanced sex ratio. Among POPs, dichlorodiphenyldichloroethylene (4,4'-DDE) and polychlorinated biphenyls (PCBs) are the most widespread and well-studied compounds. Recent studies have revealed that 4,4'-DDE is an antagonist of androgen receptor (AR). However, the mechanism of the inhibition remains elusive. CB-153 is the most common congener of PCBs, while the action of CB-153 on AR is still under debate.


RESULTS
Molecular docking and molecular dynamics (MD) approaches have been employed to study binding modes and inhibition mechanism of 4,4'-DDE and CB-153 against AR ligand binding domain (LBD). Several potential binding sites have been detected and analyzed. One possible binding site is the same binding site of AR natural ligand androgen 5α-dihydrotestosterone (DHT). Another one is on the ligand-dependent transcriptional activation function (AF2) region, which is crucial for the co-activators recruitment. Besides, a novel possible binding site was observed for POPs with low binding free energy with the receptor. Detailed interactions between ligands and the receptor have been represented. The disrupting mechanism of POPs against AR has also been discussed.


CONCLUSIONS
POPs disrupt the function of AR through binding to three possible biding sites on AR/LBD. One of them shares the same binding site of natural ligand of AR. Another one is on AF2 region. The third one is in a cleft near N-terminal of the receptor. Significantly, values of binding free energy of POPs with AR/LBD are comparable to that of natural ligand androgen DHT.
College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China. cxwangbjut@gmail.com.
Xian Jin
XJ
Xu
Ji Guo
JG
Su
Anna Rita
AR
Bizzarri
Salvatore
S
Cannistraro
Ming
M
Liu
Yi
Y
Zeng
Wei Zu
WZ
Chen
Cun Xin
CX
Wang
D001665:Binding Sites; D020134:Catalytic Domain; D003633:Dichlorodiphenyl Dichloroethylene / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000378:metabolism; D004785:Environmental Pollutants / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011078:Polychlorinated Biphenyls / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry* / Q000378:metabolism*
C410798:AR protein, human; D004785:Environmental Pollutants; D008024:Ligands; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D003633:Dichlorodiphenyl Dichloroethylene; D011078:Polychlorinated Biphenyls; C014024:2,4,5,2',4',5'-hexachlorobiphenyl