An AP Endonuclease 1–DNA Polymerase β Complex Theoretical Prediction of Interacting Surfaces 英文参考文献.docVIP

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An AP Endonuclease 1–DNA Polymerase β Complex Theoretical Prediction of Interacting Surfaces 英文参考文献.doc

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An AP Endonuclease 1–DNA Polymerase β Complex Theoretical Prediction of Interacting Surfaces 英文参考文献

AnAPEndonuclease1–DNAPolymerasebComplex: TheoreticalPredictionofInteractingSurfaces AlexejAbyzov,AlperUzun,PhyllisR.Strauss,ValentinA.Ilyin* DepartmentofBiology,NortheasternUniversity,Boston,Massachusetts,UnitedStatesofAmerica Abstract Abasic(AP)sitesinDNAarisethroughbothendogenousandexogenousmechanisms.SinceAPsitescanpreventreplication and transcription, the cell contains systems for their identification and repair. AP endonuclease (APEX1) cleaves the phosphodiesterbackbone59totheAPsite.Thecleavage,akeystepinthebaseexcisionrepairpathway,isfollowedby nucleotideinsertionandremovalofthedownstreamdeoxyribosemoiety,performedmostoftenbyDNApolymerasebeta (pol-b).Whileyeasttwo-hybridstudiesandelectrophoreticmobilityshiftassaysprovideevidenceforinteractionofAPEX1 andpol-b,thespecificsremainobscure.Wedescribeatheoreticalstudydesignedtopredictdetailedinteractingsurfaces between APEX1 and pol-b based on published co-crystal structures of each enzyme bound to DNA. Several potentially interactingcomplexeswereidentifiedbyslidingtheproteinmoleculesalongDNA:twowithpol-blocateddownstreamof APEX1 (39 to the damaged site) and three with pol-b located upstream of APEX1 (59 to the damaged site). Molecular dynamics(MD)simulations,ensuringgeometricalcomplementarityofinterfaces,enabledustopredictinteractingresidues andcalculatebindingenergies,whichintwocasesweresufficient(,210.0kcal/mol)toformastablecomplexandinone caseaweaklyinteractingcomplex.AnalysisofinterfacebehaviorduringMDsimulationandvisualinspectionofinterfaces allowedustoconcludethatcomplexeswithpol-batthe39-sideofAPEX1arethosemostlikelytooccurinvivo .Additional multiple sequence analyses of APEX1 and pol-b in related organisms identified a set of correlated mutations of specific residues at the predicted interfaces. Based on these results, we propose that pol-b in the open or closed conformation interactsandmakesastableinterfacewithAPEX1boundtoacleavedabasicsiteonthe39side.Themethoddescribedhere canbeusedforanalysisinanyDNA-me