Functional and Structural Insights Revealed by Molecular Dynamics Simulations of an Essential RNA Editing Ligase in Trypanosoma brucei 英文参考文献.docVIP

FunctionalandStructuralInsightsRevealedbyMolecular DynamicsSimulationsofanEssentialRNAEditingLigase inTrypanosomabrucei RommieE.Amaro1*,RobertV.Swift1,J.AndrewMcCammon1,2,3,4 1Department of Chemistry and Biochemistry, University of California San Diego,La Jolla, California, United States of America, 2NSF Center for Theoretical Biological Physics(CTBP),UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica,3DepartmentofPharmacology,UniversityofCaliforniaSanDiego,LaJolla, California,UnitedStatesofAmerica,4HowardHughesMedicalInstitute,UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica Abstract RNAeditingligase1(TbREL1)isrequiredforthesurvivalofboththeinsectandbloodstreamformsofTrypanosomabrucei, theparasiteresponsibleforthedevastatingtropicaldiseaseAfricansleepingsickness.ThetypeofRNAeditingthatTbREL1 is involved in is unique to the trypanosomes, and no close human homolog is known to exist. In addition, the high- resolutioncrystalstructurerevealedseveraluniquefeaturesoftheactivesite,makingthisenzymeapromisingtargetfor structure-based drug design. In this work, two 20ns atomistic molecular dynamics (MD) simulations are employed to investigate the dynamics of TbREL1, both with and without the ATP substrate present. The flexibility of the active site, dynamics of conserved residues and crystallized water molecules, and the interactions between TbREL1 and the ATP substrateareinvestigatedanddiscussedinthecontextofTbREL1’sfunction.Differencesinlocalandglobalmotionupon ATP binding suggest that two peripheral loops, unique to the trypanosomes, may be involved in interdomain signaling events. Notably, a significant structural rearrangement of the enzyme’s active site occurs during the apo simulations, opening an additional cavity adjacent to the ATP binding site that could be exploited in the development of effective inhibitors directed against this protozoan parasite. Finally, ensemble averaged electrostatics calculations over the MD si