Establishment Of A Receptor Activity Differentiation Model Based On Molecular Dynamics Simulation Enhanced By Metadynamic

Endocrine disrupting chemicals(EDCs)require only a very low concentration to produce significant adverse effects and are therefore of concern.The effects of nuclear receptor-mediated endocrine disruption are divided into two types:agonistic effect and antagonistic effect.Up to now,humans have synthesized and registered more than 142 million chemicals(http://www.cas-china.org/index.php?c=list&cs=chemical_substanc es),and the number is still rising,and a large number of them have endocrine.The substance that interferes with the effect has not yet been identified.Existing in vivo and in vitro experimental techniques are also unable to cope with the increasing number of compounds to be screened.The development of computational toxicology provides a new way to solve this problem.However,the traditional quantitative structure-activity relationship(QSAR)can only predict the activity of compounds with known activity,but it can not qualitatively distinguish the activity of compounds,and the compounds predicted by this method are often only one type of structural similarity.Compounds,when the number of compounds increases,the predicted effect will be significantly reduced.Therefore,in this study,a computational model for distinguishing the activity of a compound is first established,and then a conventional structure-activity model is used to predict the activity of the compound.In the computational simulation method,molecular dynamics simulation(Molecular Dynamic Simulation)can simulate the microscopic behavior of molecules and simulate the non-bonding and configuration changes between the two systems of interaction,thus exploring the small molecules of ligands.It is helpful to interact with biological macromolecules and to judge the stable configuration of the complex.However,the free energy plane of the molecular system often has a large number of local minimums of energy,which causes the MD simulation to sample in these confined regions for a long time.This results in the inability to sample the global minimum energy for an acceptable amount of time,or the inability to explore the entire free energy-conformation space.At this stage,people mainly improve the sampling efficiency by enhancing the sampling method to solve such problems.Metadynamic is one of them.Therefore,this study utilizes Metadynamic molecular dynamics simulation and ligand-receptor-based pharmacophore simulation to achieve the following objectives by analyzing the lowest-energy conformation after binding;(1)Studying the establishment of different classes of compounds in combination with androgen receptors The body(AR)and the peroxidase-activated receptor gamma(PPARy)post-agonistic/antagonistic activity differentiation model and quantitative prediction of compound activity.(2)It is possible to explore AR and PPARy binding antagonists.(3)Establish a differentiation model of the aromatic hydrocarbon receptor AhR activity.In view of the interference effect of PPARy,this study collected the PPARy activity data and binding activity data of the detected substances in Beijing indoor dust reported in the literature,and then used Metadynamic molecular dynamics to calculate the complex of these substances and receptors.It was found that when full agonist binding,there is only one stable conformation of PPARy,which is similar to the resolved PPARy excited conformation.After binding to the antagonist,the 12th helix of PPARy(Helix 12,H12)is far from the PPARy-LBD pocket and occupies the AF-2 region,which is similar to the antagonistic conformation of PPARa,which may hinder the binding of coactivators and lead to antagonism.Effectiveness.When a partial agonist binds to PPAR y,the free energy surface shows a state in which the free energy of the full agonist and the antagonist is superimposed.This suggests that PPARy has both agonistic and antagonistic conformations when a partial agonist binds.This also explains the fact that some agonists have a large gap in activity when their ability to bind to a full agonist is similar.Drawing on the above ideas,the Metadynamic molecular dynamics simulation was carried out for the role of AR.It has also-been found that when the agonist and the antagonist bind to the androgen receptor,there is a difference in the low energy region on the free energy plane.When AR binds to an antagonist,the H12 helix appears to be helically reduced and away from the receptor pocket,and its conformation is similar to the antagonistic crystal conformation of the glucocorticoid receptor(GR).These qualitative differentiation models do not rely on specific laboratory measurements,can efficiently and accurately identify the activity of compounds,and combine them with quantitative prediction models established by traditional QSAR to form a new prediction system for judging the anti-male activity of compounds.Significantly reduce endocrine disruption laboratory measurements,reduce work costs,and improve recognition efficiency.Finally,based on the experimental results of PCDPS and the literature results of HO/MeO-PBDE,this study used the Metadynamic simulation method to explore the activation model of AhR.Whether the ligand is an AhR agonist is determined by whether the ligand is stable after binding to the ligand by the AhR-ARNT complex in the activation model.However,it should be pointed out that due to the lack of crystal structure of AhR-LBD,caution should be exercised when applying this model.The above research promotes the use of molecular modeling methods in the field of environmental toxicology,and provides new ideas for the development of theoretical environmental chemistry.Especially in practical applications,it provides more computer-based prediction technology and methodological basis for comprehensive evaluation of the endocrine disruption effect and safety of chemicals,making the simulation method more vital in environmental science.