Probing the Mutational Interplay between Primary and Promiscuous Protein Functions A Computational-Experimental Approach 英文参考文献.docVIP

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Probing the Mutational Interplay between Primary and Promiscuous Protein Functions A Computational-Experimental Approach 英文参考文献.doc

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Probing the Mutational Interplay between Primary and Promiscuous Protein Functions A Computational-Experimental Approach 英文参考文献

ProbingtheMutationalInterplaybetweenPrimaryand PromiscuousProteinFunctions:AComputational- ExperimentalApproach HectorGarcia-Seisdedos,BeatrizIbarra-Molero,JoseM.Sanchez-Ruiz* FacultaddeCiencias,DepartamentodeQuimicaFisica,UniversidaddeGranada,Granada,Spain Abstract Proteinpromiscuityisofconsiderableinterestdueitsroleinadaptivemetabolicplasticity,itsfundamentalconnectionwith molecularevolutionandalsobecauseofitsbiotechnologicalapplications.Currentviewsontherelationbetweenprimary andpromiscuous proteinactivitiesstemlargelyfromlaboratory evolutionexperiments aimed atincreasingpromiscuous activity levels. Here, on the other hand, we attempt to assess the main features of the simultaneous modulation of the primaryandpromiscuousfunctionsduringthecourseofnaturalevolution.Thecomputational/experimentalapproachwe proposeforthistaskinvolvesthefollowingsteps:afunction-targeted,statisticalcouplinganalysisofevolutionarydatais used to determine a set of positions likely linked to the recruitment of a promiscuous activity for a new function; a combinatorial library of mutations on this set of positions is prepared and screened for both, the primary and the promiscuous activities; a partial-least-squares reconstruction of the full combinatorial space is carried out; finally, an approximation to the Pareto set of variants with optimal primary/promiscuous activities is derived. Application of the approachtotheemergenceoffoldingcatalysisinthioredoxinscaffoldsrevealsanunanticipatedscenario:diversepatterns ofprimary/promiscuousactivitymodulationarepossible,includingamoderate(butlikelysignificantinabiologicalcontext) simultaneousenhancementofbothactivities.Weshowthatthisscenariocanbemostsimplyexplainedonthebasisofthe conformationaldiversityhypothesis,althoughalternativeinterpretationscannotberuledout.Overall,theresultsreported mayhelpclarifythemechanismsoftheevolutionofnewfunctions.Fromadifferentviewpoint,thepartial-least-squares- reconstruction/Pareto-set-prediction approach we hav