Molecular Dynamics Study On Bisphenol A Susceptibility Based On SNP Estrogen Receptor Mutation

The estrogen receptor belongs to the superfamily of ligand inducible nuclear receptors transcription factors,including N-terminal region,DNA binding domain(DBD),the hinge region and C-terminal ligand binding domain(LBD).Exogenous or endogenous compounds ligand binding changes the structure and function of LBD,and thus affect its transcription activity.In the estrogen receptor N-terminal region,DBD,the hinge region and LBD,Many single nucleotide polymorphisms related to the susceptibility have been found and influenced transcription activity of DNA through conformation change.Therefore there must be an interactive relationship between different regions in the estrogen receptor to influence transcription activity though transferring domain-domain informations.Starting from this point,we focus on the bisphenol A susceptibility of wild estrogen receptor with its corresponding single nucleotide polymorphisms K303R and Y537N mutation systems in this paper and explore the molecular mechanisms of bisphenol A susceptibility based on the mutant estrogen receptors.We generated three dimensional structures of estrogen receptor including DBD,the hinge region and LBD by homologous modeling methods;bisphenol A was docked into wild estrogen receptor,K303R and Y537N mutant estrogen receptors followed by molecular dynamics method for simulating and analyzing the three systems.Our study shows bisphenol A influences transcription activity mainly through conformation change of DBD and LBD in the multidomain estrogen receptor which alters domain-domain interactions.K303R and Y537N mutation make dimmer interface interaction of LBDs enhanced;then lead to hydrogen bonds interaction increased between the LBD and DBD interface and DNA binding activity increased;eventually result in bisphenol A susceptibility enhanced.In conclusion,this paper not only discusses the molecular mechanism of estrogen receptor single nucleotide polymorphisms associated with bisphenol A susceptibility from molecular level but also provides theoretical guidance for the study of multidomain structure and susceptibility to environmental pollutants in the other nuclear receptor superfamily proteins.