Tautomeric Effect of Histidine on the Monomeric Structure of Amyloid β-Peptide(1–42) Hu Shi.pdf

该【Tautomeric Effect of Histidine on the Monomeric Structure of Amyloid β-Peptide(1–42) Hu Shi 】是由【李十儿】上传分享，文档一共【7】页，该文档可以免费在线阅读，需要了解更多关于【Tautomeric Effect of Histidine on the Monomeric Structure of Amyloid β-Peptide(1–42) Hu Shi 】的内容，可以使用淘豆网的站内搜索功能，选择自己适合的文档，以下文字是截取该文章内的部分文字，如需要获得完整电子版，请下载此文档到您的设备，方便您编辑和打印。ResearchArticlepubs./chemneuroTautomericE?ectofHistidineontheMonomericStructureofAmyloidβ?Peptide(1?42)HuShiandJinYongLee*DepartmentofChemistry,SungkyunkwanUniversity,Suwon440-746,Korea*SSupportingInformationABSTRACT:Tautomericstateofhistidineisoneofthefactorsthatin?uencethestructuralandaggregationpropertiesofamyloidβ(Aβ)-(1?42)peptideincomparisonwithAβ(1?40)-exchangemoleculardynamicssimulationsresultsshowthatthesheetcontentofeachtautomericisomerinAβ(1?42)monomerisslightlyhigherthanthatinAβ(1?40)monomerexceptHis6(δ)-His13(δ)-His14(δ)(δδδ)isomer,implyinghigheraggregationtendencyinAβ(1?42),(εεε),(εδε),(εδδ),and(δδε),itiscon?rmedthatantiparallelβ-sheetsof(εδδ)wereformedatK16-E22(?%),N27-A30exceptG29(?%),andM35-I41exceptG37(?%).Furthermore,(εδδ)estructuraltransformationduetononobstructinginteractionsbetweenK16and/?ectofAβ(1?42)peptidetoeAlzheimer’:Tautomerice?ect,amyloid(1?42)peptide,automer,sheetstructure,proteinmisfolding,aggregationlzheimer’sdisease(AD)monformofdramatically?guredoutafteralargenumberofexperimentalAdementia,?brils,Aβ(1?40)andAβ(1?42)e?-strandorthogonaltopropertiesofADaredepositsofsenileplaques(po-theaxisof?bril,whichwerestablebyintramolecularand?nent:amyloidβ(Aβ)-peptidefragments)andentanglementofintermolecularinteractionsbetweenβ--tau-?43residues,onformation,di?(APP)bySomestudiesreportedthatAβ(1?40)adoptedβ-hairpinwithβ-andγ-,lusteraminoacidfrom1to40(Aβ(1?40))wasreportedtoexist90%,(CHC,L17-A21)andA30-V36,19,20However,Aβ(1?42)andthatofAβfragmentaminoacidfrom1to42(Aβ(1?42))showedthreeantiparallelβ-strandinCHC,A30-V36,and??is10%.57AbnormalchangesinAPPandγ-secretasearecriticalV39??guredoutβ-hairpinscanbe??tocuriouspathogenicityoftheAβ(1?42)/Aβ(1?40)(1?42)butnot/lessinAβ(1?40).2326ThesameComparedwithAβ(1?40),Aβ(1?42)hassameprimaryaminotendencyisthatAβ(1?42)?erenceisthatonlytwosheetconformationthanAβ(1?40)underthesameenviron--terminusofAβ(1?42).Despitesuchaslightdi?erence,ThebalancebetweenAβproductionandclearancehasbeenAβ(1?42)umulationprocedureofsenileformaggregatesand?brils,,,,u-hydrophobicresiduesinC-terminuscansigni?cantlyin?uencemulationofAβproductionwillpromotethegenerationof27,28thestructuralpropertiesbetweenAβ(1?40)andAβ(1?42),,manyfactors,suchaspHenviron-?ment,APPmutation,β-/γ-secretaseactivity,andmetalions,canwhichwasconrmedbythedistinctmechanismofoligome-?13,14?,properchemicaltoolsMonomericformsofAβhavebeenclassi?edasintrinsicallydisorderedpeptides(IDPs),implyingthatthereisdiversesetofReceived:November3,2016epted:November16,,similarstructuralmorphologieswerePublished:November16,2016?XXXXAmericanChemicalSocietyADOI:.,XXX,XXX?XXXACSChemicalNeuroscienceResearchArticlewereobtainedtoidentifypathologicalfactors,suchasmetals,Aβ,metal-Aβ,reactiveoxygenspecies,,manystudieshavecon?rmedonditioncanpromoteβ-sheetformationand?,contrarytoothertitratableaminoacids,histidineresidueisinuncertaincondition(tautomerstate).39Intheunprotonatedstate,theimidazolesidechainofhistidineexistsintwoforms,Nε?Htautomer(NεH,denotedasε)andNδ?Htautomer(NδH,denotedasδ),andthepopulationratio(ε/δ)wasreportedtobearound?1:,theslightlyenvironmentalchangecana?ecttheprobabilitiesofε/,thestructuralfeaturesbinationbyεand/orδisomersofhistidineresiduescannotbeelucidatedinexperiment,inthiscase,computationaldynamicssimulationwouldbeanappropriateβ??(142)ineachisomerasparedwithAβ(1?40).SheetcontentofAβ(1?40)isobtainedInparticular,,only?exiblefoldedstructurewasobtainedinβ?43β-AcA(1323)-lengthstudy,Aβ(1?42)monomer,wecitedsheetcontentofAβ(1?40)β?ourpreviousmonomericA(140)studysuggestedthatstruc-?εδ-ofAβ(1?42)monomerisgenerallyhigherthanthatofδδδδbinations.()(isomerlocatedatH6,H13,andH14Aβ(1?40)monomerineachisomerexceptfor(δδδ))adoptsdominatingthree-strandsformationwithisworthtomentionthatεformationismoreabundantthanδ?interactionsbetweenR5-D7andL34-G38,andL17-,wemay44εδL34-,thetransitionbetweenandconcludethatthesheetcontentofAβ(1?42)isgenerallyisomerstatesofhistidineisfastthanmisfoldingprocedureofhigherthanthatofAβ(1?40),transitionissensitivetoenvironmentcon-conclusionisinagreementwiththefactthatAβ(1?42),itisstillunclearbecauseAispartofaclasshighertendencytoformsheetstructurethanAβ(1?40)inboth?,(1?40)?,(δδδ),inAβ(1?42)monomer,(εδδ)%.TheorderofsheetcontentinsuchhydrogenbondinteractionmayobstructinteractionAβ(1?42)monomerwas(εδδ)>(εδε)>(εεε)>(δδε)>betweencentralL17-A21regionandC-(δεε)>(δεδ)>(δδδ)>(εεδ)%,%,β?parethestructuralfeaturesofA(142)%,%,%,%,%,%,?β?comparisonwithA(140)becauseA(142)hasadrama-InordertoevaluatestructuralpropertiesinAβ(1?42)?ticallyhigherpropensitytoformbrilsandisknowntocausemonomer,partialsecondarystructure(allofthedatagiveninβ?11,12serioustoxicitytoneuronsthanA(140).Inthisregard,TableS2)?ontentparallelβ-bridgebetweenH6andH13(%)inβ?A(142)byreplica-exchangemoleculardynamics(REMD)(εεε)isomerandhighcontentantiparallelβ-bridgebetweenparedwithstandardmoleculardynamicsH6andV36(%)in(δδδ)isomer,theseisomersmaynotsimulation,REMDisanenhancedsamplingmethodbyallowingbecrucialtotheaggregationofAβ(1?42),in(εδδ)?-isomer,antiparallelβ-sheetscanbefoundinK16-E22(?βstandingself-%),N27-A30expectG29(?%),andM35-I41exceptG37(?%).Meanwhile,α-helixislocatedat■RESULTSANDDISCUSSIONK16-?%,atN27-?%,andatM35-?%.,in(εεε)isomer,aslightdi?erenceisthatantiparalleleptanceratiois20?22%.Aftercarefullyevaluatingtheβ-ursatL17-A21(?%),A30-V36(?convergence(FigureS1andTableS1),%),andV39?I41(?%).Thestructuralfeatures?(εεε)isomerisinagreementwithpreviousstudies,,in(δδε)isomer,peptidesiscriticaltoformoligomersand?brilsfromnativeantiparallelβ-sheetcanbefoundinK17-A21(?%),,thesheetformationcontentofeachG33-V36(?%),andV39?I41(?%).?ndthatsheetcontrary,in(εδε)isomer,antiparallelβ-sheetappearsinE3-H6contentsweredramaticallydi?erentin8isomersofAβ(1?42)(?%),V18-D23(?%),andG33-I41(?%).monomer,whichissimilartoAβ(1?40)monomer,44implyingThedi?erenceisthatβ-sheetwasobtainedinN-?ectofhistidinecanin?uencestructuralandMoreover,di?erenttoantiparallelβ-sheet,in(δεδ)isomer,-ursatE11-K16(content:?%)andcomparethesheetcontentbetweenAβ(1?40)monomerandV36?I41(content:?%).ThereresultsdemonstrateBDOI:.,XXX,XXX??-sheet(A),antiparallelsheet(B),andα-helix(C)?of5?viabest-?tcoordinateroot-mean-(RMSD)-A21region,thegreenbandrepresentsthesheetstructure,andthebluesphererepresentstheN-?erenceisomersexhibitedsigni??veconformationalstatesandtheirprob-Toevaluatetherolesofhistidinein(εεε),(εδε),(εδδ),?erenttosheet-(δδε)isomers,hydrogenbondpopulationsrelatedtohistidinerichpropertiesof(δδδ)isomerinAβ(1?40)monomer,?ndoutK16(δδδ)isomerofAβ(1?42)monomeradoptsahelix-andL17interactwithH13in(εεε)isomerwithcontentrangedominatingconformerwithS1(%%.Suchbackbonehydrogenbondswerestate1)%.Suchahelix-dominatingisomermaynotbealsofoundinAβ(1?40)monomerstudy,whichwouldtoxicbecausetoxicityispresumedtobeemergedundercon-heinteractionbetweencentralL17-A21regionandformationalswitchingfromα-helixorrandomcoiltosheetC-,suchspeci?,therestofthempreferrednon-interactionswerealsoobtainedin(εδε)(content:?dominatingstructureswithsigni?%),and(δδε)(content:?%).Therefore,onecancontentofS1in(εεε),(εεδ),(εδε),(εδδ),(δεε),(δεδ),andconcludethat(εδδ)isomerwithoutsuchintervening(δδε)%,%,%,%,%,%,%,,althoughthesearediverseconfor-,(εεε),(εδε),(εδδ),and(δδε)(FigureS2byclusterDespiteIDPphenomenawereobtainedin(εεε),(εδε),analysisonthebasisofallatom)showhighersheetcontentas(εδδ),and(δδε)isomers,inordertofurtheruncoverstructuralcomparedwith(εεδ),(δεε),and(δεδ).properties,STRIDEalgorithmwasemployedtoselectsheetCDOI:.,XXX,XXX?(εεε),(εδε),(εδδ),and(δδε),theX-andY-axisrepresenttheresiduenumberindex,andcolor(Z-axis)(εεε),(εδε),(εδδ),and(δδε).obtainedinE3-R5,Q15-E22,N27-A30exceptG29,andAsaresult,5020,7475,14474,and5119frames(total:20000,M35-,incontactmapanalysis,onlysheet_(εδδ)20000,30000,and20000frames,respectively)werecollectedshowsregularbackboneinteractionbetweenK16--I41,aswellasbetweenF19-E22andN27?(denotedtosheet_isomer),secondarystructuresofsheet_(εεε),phenomenoncon?rmedthat(εδδ)isomermayplayacriticalsheet_(εδε),sheet_(εδδ),andsheet_(δδε)areshowninFigure