Allosteric Analysis of Glucocorticoid Receptor-DNA Interface Induced by Cyclic Py-Im Polyamide A Molecular Dynamics Simulation Study 英文参考文献.docVIP

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Allosteric Analysis of Glucocorticoid Receptor-DNA Interface Induced by Cyclic Py-Im Polyamide A Molecular Dynamics Simulation Study 英文参考文献.doc

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Allosteric Analysis of Glucocorticoid Receptor-DNA Interface Induced by Cyclic Py-Im Polyamide A Molecular Dynamics Simulation Study 英文参考文献

AllostericAnalysisofGlucocorticoidReceptor-DNA InterfaceInducedbyCyclicPy-ImPolyamide:A MolecularDynamicsSimulationStudy YaruWang,NaMa,YanWang*,GuangjuChen* CollegeofChemistry,BeijingNormalUniversity,Beijing,People’sRepublicChina Abstract Background:Ithasbeenextensivelydevelopedinrecentyearsthatcell-permeablesmallmolecules,suchaspolyamide,can beprogrammedtodisrupttranscriptionfactor-DNAinterfacesandcansilenceaberrantgeneexpression.Forexample,cyclic pyrrole-imidazole polyamide that competes with glucocorticoid receptor (GR) for binding to glucocorticoid response elementscouldbeexpectedtoaffecttheDNAdependentbindingbyinterferingwiththeprotein-DNAinterface.However, how such small molecules affect the transcription factor-DNA interfaces and gene regulatory pathways through DNA structuredistortionisnotfullyunderstoodsofar. Methodology/PrincipalFindings:Inthepresentwork,wehaveconstructedsomemodels,especiallytheternarymodelof polyamides+DNA+GR DNA-binding domain (GRDBD) dimer, and carried out molecular dynamics simulations and free energycalculationsforthemtoaddresshowpolyamidemoleculesdisrupttheGRDBDandDNAinterfacewhenpolyamide andproteinbindatthesamesitesonoppositegroovesofDNA. Conclusions/Significance:WefoundthatthecyclicpolyamidebindinginminorgrooveofDNAcaninducealargestructural perturbationofDNA,i.e.a.4A? wideningoftheDNAminorgrooveandacompressionofthemajorgroovebymorethan ? + 4AascomparedwiththeDNAmoleculeintheGRDBDdimer DNAcomplex.Furtherinvestigationsfortheternarysystem ofpolyamides+DNA+GRDBDdimerandthebinarysystemofallostericDNA+GRDBDdimerrevealedthatthecompressionof DNAmajorgroovesurfacecausesGRDBDtomoveawayfromtheDNAmajorgroovewiththeinitialaveragedistanceof ,4A?tothefinalaveragedistanceof,10A?during40nssimulationcourse.Therefore,thisstudystraightforwardexplores howsmallmoleculetargetingspecificsitesintheDNAminorgroovedisruptsthetranscriptionfactor-DNAinterfaceinDNA majorgroove,andconsequentlymodulatesgeneexpression. Citation:WangY,MaN,WangY,ChenG(2012)