Ras Conformational Switching Simulating Nucleotide-Dependent Conformational Transitions with Accelerated Molecular Dynamics 英文参考文献.docVIP

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Ras Conformational Switching Simulating Nucleotide-Dependent Conformational Transitions with Accelerated Molecular Dynamics 英文参考文献.doc

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Ras Conformational Switching Simulating Nucleotide-Dependent Conformational Transitions with Accelerated Molecular Dynamics 英文参考文献

RasConformationalSwitching:SimulatingNucleotide- DependentConformationalTransitionswithAccelerated MolecularDynamics BarryJ.Grant1.*,AlemayehuA.Gorfe1.*,J.AndrewMcCammon1,2,3 1DepartmentofChemistryandBiochemistryandCenterforTheoreticalBiologicalPhysics,UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica, 2Howard Hughes Medical Institute, University of California San Diego, La Jolla, California, United States of America, 3Department of Pharmacology, University of CaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica Abstract RasmediatessignalingpathwayscontrollingcellproliferationanddevelopmentbycyclingbetweenGTP-andGDP-bound activeandinactiveconformationalstates.Understandingthecompletereactionpathofthisconformationalchangeandits intermediary structures is critical to understanding Ras signaling. We characterize nucleotide-dependent conformational transitionusingmultiple-barrier-crossingacceleratedmoleculardynamics(aMD)simulations.Thesetransitions,achievedfor thefirsttimeforwild-typeRas,areimpossibletoobservewithclassicalmoleculardynamics(cMD)simulationsduetothe largeenergeticbarrierbetweenendstates.Mappingthereactionpathontoaconformerplotdescribingthedistributionof the crystallographic structures enabled identification of highly populated intermediate structures. These structures have uniqueswitchorientations(residues25–40and57–75)intermediatebetweenGTPandGDPstates,ordistinctloop3(46–49), loop7 (105–110), and a5 C-terminus (159–166) conformations distal from the nucleotide-binding site. In addition, these barrier-crossingtrajectoriespredictnovelnucleotide-dependentcorrelatedmotions,includingcorrelationsofa 2(residues 66–74) with a3-loop7 (93–110), loop2 (26–37) with loop10 (145–151), and loop3 (46–49) with a5 (152–167). The interconversion between newly identified Ras conformations revealed by this study advances our mechanistic understanding of Ras function. In addition, the pattern of correlated motions provides new evidence for a dy