生物大分子结构与功能相互作用力

第一章：蛋白质的结构层次当前1页，总共86页。1,thesecondarystructures2,Supersecondarystructuresanddomains3,Toolstoinvestigatetheproteinconformation4,globularproteinsandSCOP5,fibrousproteins当前2页，总共86页。ProteinSecondaryStructure■Secondarystructureistheregulararrangementofaminoacidresiduesinasegmentofapolypeptidechain,inwhicheachresidueisspatiallyrelatedtoitsneighborsinthesameway.■Themostcommonsecondarystructuresaretheαhelix,theβ

conformation,andβ

turns.■Thesecondarystructureofapolypeptidesegmentcanbecompletelydefinediftheφand

ψanglesareknownforallaminoacidresiduesinthatsegment.当前3页，总共86页。10papersfromLinusPaulingandcolleaguespublishedinPNAS,1951当前4页，总共86页。αhelix310helixπ

helix:theoreticallypossible,butneverfoundintheproteinsßsheet:parallelandanti-parallel当前5页，总共86页。αhelixßsheet3.613helix当前6页，总共86页。Parametersoffiveactualortheoreticalsecondarystructures:当前7页，总共86页。αhelix:

thebackboneofthepolypeptidechainisextendedintohelicalstructureWhichIsbuiltupfromonecontinuousregion.αhelix当前8页，总共86页。φ,ψanglepairapproximately-60°and-50°.Thelengthrangfrom4or5to44residues.Theaveragelengthisaround10residues

当前9页，总共86页。3.6residuesperturnwithhydrogenbondsbetweenC’=OofresiduesnandNHofresiduesn+4.Theendofαhelicesarepolarandarealmostatthesurfaceofproteinmolecules当前10页，总共86页。310helixπ

helix4.416helixN+53residuesperturnanda10atomsbetweenthehydrogenbonddonorandacceptor,N+3当前11页，总共86页。Idealizedhelices:当前12页，总共86页。Hydrogenbondingpatternsforfourhelices

273103.6134.414当前13页，总共86页。当前14页，总共86页。Theαhelixhasadipolemoment1.Theoveralleffectisasignificantnetdipolefortheαhelix.Thatgivesapartialpositivechargeattheaminoend

apartialnegativechargeattheCarboxylend(0.5-0.7unitcharge)2.Unitchargeateachendattractligandsofoppositecharge.PhosphategroupsfrequentlybindattheN-terminalofαhelix.Incontrast,positivechargeligandsrarelybindatC-teminal.当前15页，总共86页。Someaminoacidsarepreferredinαhelix:Ala(A),Glu(E),Leu(L),andMet(M)

aregoodαhelicesformers.2)

Pro(P),Gly(G),Tyr(Y)andSer(S)

areveryPoorformers3)Themostcommonlocationforanαhelixinaproteinstructureisalongtheoutsideoftheprotein,withonesidefacingthesolutionandtheothersidefacingthehydrophobicinterioroftheprotein.4)αhelicesthatacrossmembranareinaHydrophobicenvironment,mostoftheirsideChainsarehydrophobic当前16页，总共86页。当前17页，总共86页。当前18页，总共86页。Saccharomycescerevisiaemitochondrialthioredoxin3Baoetal.当前19页，总共86页。MembraneProteinJ.Deisenhofer,H.MichelScience(245):1463,1989J.Dersenhofer,O.Epp,K.Miki,R.Huber,H.Michel,Nature(318):618,1985J.Deisenhofer,O.Epp,K.Miki,R.Huber,H.Michel,J.Mol.Biol.(180):385,1984H.MichelJ.Mol.Biol.(158):567,1982FirstMembraneProteinStructure:PhotosyntheticReactionCenterofRhodopseudomonasvirdis

红假单胞菌Complex(foursubunits)solvedin1985(1PRC)NobelChemistryPrizewasawardedtoJ.Deisenhofer,R.Huber,H.Michelin1988.当前20页，总共86页。1)βsheet:

thebackboneofthepolypeptidechainisextendedintoa

zigzagstructure.2)

βsheet

isbuiltupfromacombinationofseveralregionsofthepolypeptidechain.3)Thelengthrangfrom5to10residues.β

sheet当前21页，总共86页。当前22页，总共86页。Theaminoacidecanallruninthesamebiochemicaldirection,amioterminaltocarboxyterminalTheaminoacidcanhavealternatingdirections,theN-terminaltoC-terminalfollowbyC-terminaltoN-terminal当前23页，总共86页。Twoformshaveadistinctivepatternofhydrogen-bondingParallelAntiparallelTheβsheetthatareformedfromseveralβstrandsare

“pleated”当前24页，总共86页。βsheetcanalsocombineintomixedβsheet(About20%ofknownproteinstructuresaremixed)当前25页，总共86页。当前26页，总共86页。Almostalltheβsheethavetwiststrands.This

twisthasthesamehandedness

(right-handed)φ,ψangleswithinthebroadstructurallyallowedregion当前27页，总共86页。当前28页，总共86页。theDouble-headedArrowheadProteaseInhibitorA

Baoetal.当前29页，总共86页。当前30页，总共86页。LoopregionfrequentlyparticipateinformingbindingsitesandenzymeactivesitesLoopregionsareatthesurfaceofproteinmoleculesHairpinloops当前31页，总共86页。Hydrogenbondbetweentheoxygenof1stcarboxylgroupandhydrogenofthe4thaminogroupβ-turns:

connecttheendsoftwoadjacentsegmentsofanantiparallelβsheet.当前32页，总共86页。当前33页，总共86页。Productsof13genesinvolvedinpeptidyl-prolylcis-transisomeraseactivitythecommonpresenceofProandGlyresiduesinβturnsβ

turns当前34页，总共86页。

γ

turnHydrogenbondbetweentheoxygenof1stcarboxylgroupandhydrogenofthe3rdaminogroup当前35页，总共86页。ARamachandranplot当前36页，总共86页。当前37页，总共86页。SchematicpicturesofproteinshighlightsecondarystructureSimplifyFacilitateseeingsimilaritybetweenproteinsHelicessometimescylinders当前38页，总共86页。TopologydiagramsareusefulforclassificationofproteinstructuresShowthedirectionofeachβstrandandthewaythestrandsareconnectedtoeachotheralongthepolypeptidechain当前39页，总共86页。1,Thesecondarystructures2,Supersecondarystructuresanddomains

3,Toolstoinvestigatetheproteinconformation4,globularproteinsandSCOP5,fibrousproteins当前40页，总共86页。Supersecondarystructures,alsocalledmotifsorsimplyfolds,

areparticularlystablearrangementsofseveralelementsofsecondarystructureandtheconnectionsbetweenthem.当前41页，总共86页。Twoαhelicesthatareconnectedbyashortloopregion.A:helix-turn-helixmotifisspecificforDNAbindingB:thecalciumbindingmotifispresentinmanyproteinsWhosefunctionisregulatedbycalcium.当前42页，总共86页。Thecalcium-bindingmotifissymbolizedbyrighthandExample:thecalciumisboundtothemotifinthetroponin-CThecalcium-bindingmotifissymbolizedbyarighthand.ThismotifiscalledanEFhandbecausethefifthandsixthhelicesfromtheaminoterminusinstructureOfparavalbumin(inmusclerelaxationfoundin1973)whichalabeledEandF,arepartsofthestructurethatwereoriginalusedtoillustratecalciumbindingbythismotif.Theloopregionbetweenthetwoahelicesbindsthecalciumatom.CarboxylsidechainsfromAspandGlu,main-chainC’=OandH2Ofromligandstometalatom.Thehelix-loop-helixmotifprovidesascaffoldThatholdsthecalciumligandinproperpositiontobendandreleasecalcium.c)Thestructureoftroponin-CisbuiltupfromfourEFmotifs.当前43页，总共86页。当前44页，总共86页。Hairpinβmotif(Nospecificfunction)ThestrongpreferenceforβstrandstobeadjacentinβsheetswhentheyareadjacentintheaminoacidSequenceandthustoformahairpinβmotif.Thelengthoftheloopregionbetweentheβstrandsverybutaregenerallyfrom2to5residueslong.Thereisnospecificfunctionassociatedwiththismotif.当前45页，总共86页。Twoexamples:a)bovintrypsininhibitor;b)snakevenomerabutoxin当前46页，总共86页。TheGreekkeymotifExample:theenzymeStaphylococcusnuclease,anenzymethatdegradesDNATheGreekkeymotifisnotassociatedwithanyspecificfunction,Butitoccursfrequentlyinproteinstructures.

当前47页，总共86页。The

β-α-βmotifcontainstwoparallelβstrandsThisloopisofteninvolvedinFormingthefunctionalbindingsite,oractivesite.Theloopregionscanbeofverydifferentlengths,from1or2residuestoover100.ThetwoloopshaveDifferentfunctions.Theloopthatconnectsthecarboxylendoftheβstrandwithaminoendofαhelixisofteninvolvedinformingthefunctionalbindingsite,oractivesite,ofthesestructures.Theseloopregionsthususuallyhaveconservedaminoacidsequencesinhomologousproteins.Incontrast,theotherloophasnotyetfoundtocontributetoanactivesite.当前48页，总共86页。Connectionsbetweenβstrandsinlayeredβsheets当前49页，总共86页。Twoarrangementsofβ

strandsstabilizedbythetendencyofthestrandstotwist.Hemolysin(apore-formingtoxinthatkillsacellbycreatingaholeinitsmembrane)fromthebacteriumStaphylococcusaureus(PDB7AHL).photolyase(aproteinthatrepairscertaintypesofDNAdamage)fromE.coli(PDB1DNP).当前50页，总共86页。

氨基酸顺序相邻的花样通常在三维结构上也靠近

当前51页，总共86页。RNA结合蛋白(ROP)的四个-螺旋折叠为一个四螺旋束

当前52页，总共86页。

-螺旋的球状折叠

当前53页，总共86页。

反平行的-链形成桶结构

当前54页，总共86页。上-下--回折桶结构

当前55页，总共86页。

反平行-结构中的希腊图案花样

当前56页，总共86页。果冻卷饼状桶(jellyrollbarrels)

结构花样

当前57页，总共86页。

/

TIM桶结构开放扭曲的/结构

当前58页，总共86页。开放扭曲的α/β结构中的结合部位形成裂缝

当前59页，总共86页。Proteinmoleculesareorganizedinastructuralhierarchy(等级）PrimarystructureSecondarystructureTertiarystructure(domains)Quaternarystructure当前60页，总共86页。LargepolypeptidechainsfoldintoseveraldomainsEGF:domainsthatarehomologoustoepidermal(表皮细胞）growthfactor(53aminoacids)当前61页，总共86页。Constructinglargemotifsfromsmallerones当前62页，总共86页。1,re-visitofthesecondarystructures2,Supersecondarystructuresanddomains3,Toolstoinvestigatetheproteinconformation4,globularproteinsandSCOP5,fibrousproteins当前63页，总共86页。Helpfulwebsites:1,PDB(ProteinDataBank)2,SCOP(StructuralClassificationofProteins)3,comparisonofproteinstructuresin3D当前64页，总共86页。A,X-raycrystallographyB,NMR(nuclearmagneticresonance)C,CD(circulardichroism)D,…当前65页，总共86页。Computerprograms当前66页，总共86页。NMRandNobelPrice:1944:I.I.Rabi,suggeststhatinformationaboutatoms'nucleicanbeobtainedbystudyingtheinternalmagnetismofprotons.Thisformsthefundamentalbasisfortoday'sresonanceimagingtechnologies1952:

PhysicistsE.Purcell(Harvard)andF.Bloch(Stanford)discoverNuclearMagneticResonance(NMR).

1991:R.Ernst,AdvancesinNMRcouldleadtotheabilitytodirectlyobservethechemicalactionofmedicationinthebody.2002:JohnB.Fenn,KoichiTanaka,KurtWüthrichforthedevelopmentofnuclearmagneticresonancespectroscopyfordeterminingthethree-dimensionalstructureofbiologicalmacromoleculesinsolution"当前67页，总共86页。

TheNobelPrizeinChemistry2002"forthedevelopmentofmethodsforidentificationandstructureanalysesofbiologicalmacromolecules""fortheirdevelopmentofsoftdesorptionionisationmethodsformassspectrometricanalysesofbiologicalmacromolecules""forhisdevelopmentofnuclearmagneticresonancespectroscopyfordeterminingthethree-dimensionalstructureofbiologicalmacromoleculesinsolution"

JohnB.Fenn

KoichiTanaka

KurtWüthrich

1/4oftheprize

1/4oftheprize

1/2oftheprizeUSAJapanSwitzerlandVirginiaCommonwealthUniversity

Richmond,VA,USAShimadzuCorp.

Kyoto,JapanEidgenössischeTechnischeHochschule(SwissFederalInstituteofTechnology)

Zurich,Switzerland;TheScrippsResearchInstitute

LaJolla,CA,USAb.1917b.1959b.1938当前68页，总共86页。当前69页，总共86页。当前70页，总共86页。3Dstructurecomparison:

当前71页，总共86页。1,re-visitofthesecondarystructures2,Toolstoinvestigatetheproteinconformation3,Supersecondarystructuresanddomains4,globularproteinsandSCOP5,fibrousproteins当前72页，总共86页。Inconsideringthesehigherlevelsofstructure,itisusefultoclassifyproteinsintotwomajorgroups:fibrousproteins,havingpolypeptidechainsarrangedinlongstrandsorsheets,andglobularproteins,havingpolypeptidechainsfoldedintoasphericalorglobularshape.当前73页，总共86页。Thetwogroupsdifferfunctionallyfromeachother:fibrousproteinsprovidesupport,shape,andexternalprotectiontovertebratesglobularproteins:mostenzymesandregulatoryproteinsThetwogroupsarestructurallydistinct:

fibrousproteinsusuallyconsistlargelyofasingletypeofsecondarystructure;globularproteinsoftencontainseveraltypesofsecondarystructure.当前74页，总共86页。StructuralClassificationofProteins(SCOP)(globularproteins)1,Allα2,Allβ3,α/β4,α+β当前75页，总共86页。Proteinfamilyandsuperfamily当前76页，总共86页。当前77页，总共86页。当前78页，总共86页。α/