A Role for Both Conformational Selection and Induced Fit in Ligand Binding by the LAO Protein 英文参考文献.docVIP

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A Role for Both Conformational Selection and Induced Fit in Ligand Binding by the LAO Protein 英文参考文献.doc

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A Role for Both Conformational Selection and Induced Fit in Ligand Binding by the LAO Protein 英文参考文献

ARoleforBothConformationalSelectionandInduced FitinLigandBindingbytheLAOProtein Daniel-AdrianoSilva1,2,GregoryR.Bowman3,AlejandroSosa-Peinado2,XuhuiHuang1* 1Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, 2Department of Biochemistry, Medicine School,UniversidadNacionalAuto′nomadeMe′xico,Me′xico D.F.,Me′xico,3DepartmentofChemistry,StanfordUniversity,Stanford,California,UnitedStatesofAmerica Abstract Molecularrecognitionisdeterminedbythestructureanddynamicsofboth aproteinanditsligand,butitis difficultto directly assess the role of each of these players. In this study, we use Markov State Models (MSMs) built from atomistic simulationstoelucidatethemechanismbywhichtheLysine-,Arginine-,Ornithine-binding(LAO)proteinbindstoitsligand. Weshowthatourmodelcanpredicttheboundstate,bindingfreeenergy,andassociationratewithreasonableaccuracy andthenusethemodeltodissectthebindingmechanism.Inthepast,thisbindingeventhasoftenbeenassumedtooccur via an induced fit mechanism because the protein’s binding site is completely closed in the bound state, making it impossiblefortheligandtoenterthebindingsiteaftertheproteinhasadoptedtheclosedconformation.Morecomplex mechanisms havealso beenhypothesized, but these haveremained controversial. Here, we areable to directly observe rolesforboththeconformationalselectionandinducedfitmechanismsinLAObinding.First,theLAOproteintendstoform apartiallyclosedencountercomplexviaconformationalselection(thatis,theapoproteincansamplethisstate),though theinducedfitmechanismcanalsoplayarolehere.Then,interactionswiththeligandcaninduceatransitiontothebound state.Basedontheseresults,weproposethatMSMsbuiltfromatomisticsimulationsmaybeapowerfulwayofdissecting ligand-bindingmechanismsandmayeventuallyfacilitateadeeperunderstandingofallosteryaswellasthepredictionof newprotein-ligandinteractions,animportantstepindrugdiscovery. Citation: Silva D-A, Bowman GR, Sosa-Peinado A, Huang X (2011) A Rol