Nucleotide Binding Switches the Information Flow in Ras GTPases 英文参考文献.docVIP

NucleotideBindingSwitchestheInformationFlowinRas GTPases FrancescoRaimondi1,2,GuillemPortella3,ModestoOrozco3,4,FrancescaFanelli1,2 * 1DepartmentofChemistry,UniversityofModenaandReggioEmilia,Modena,Italy,2DulbeccoTelethonInstitute(DTI),UniversityofModenaandReggioEmilia,Modena, Italy, 3Molecular Modeling and Bioinformatics Unit, IRB-BSC Joint Research Program in Computational Biology, Institute for Research in Biomedicine, and Barcelona SupercomputingCenter,Barcelona,Spain,4NationalInstituteofBioinformatics,ParcCient?′ficdeBarcelona,Barcelona,Spain Abstract The Ras superfamily comprises many guanine nucleotide-binding proteins (G proteins) that are essential to intracellular signaltransduction.Theguaninenucleotide-dependentintrinsicflexibilitypatternsoffiveGproteinswereinvestigatedin atomicdetailthroughMolecularDynamicssimulationsoftheGDP-andGTP-boundstates(SGDPandSGTP,respectively).For alltheconsideredsystems,theintrinsicflexibilityofSGDPwashigherthanthatofSGTP,suggestingthatGuanineExchange Factor (GEF) recognition and nucleotide switch require higher amplitude motions than effector recognition or GTP hydrolysis. Functional mode, dynamic domain, and interaction energy correlation analyses highlighted significant differences in the dynamics of small G proteins and Ga proteins, especially in the inactive state. Indeed, SGDP of Gat , is characterized by a more extensive energy coupling between nucleotide binding site and distal regions involved in GEF recognitioncomparedtosmallGproteins,whichattenuatesintheactivestate.Moreover,mechanicallydistinctdomains implicatedinnucleotideswitchcouldbedetectedinthepresenceofGDPbutnotinthepresenceofGTP.Finally,insmallG proteins,functionalmodesaremoredetectableintheinactivestatethanintheactiveoneandinvolvechangesinsolvent exposure of two highly conserved amino acids in switches I and II involved in GEF recognition. The average solvent exposureoftheseaminoacidscorrelatesinturnwiththerateofGDPrelease,suggestingforthemeitherdirectori