Emergence of Protein Fold Families through Rational Design 英文参考文献.docVIP

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Emergence of Protein Fold Families through Rational Design 英文参考文献.doc

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Emergence of Protein Fold Families through Rational Design 英文参考文献

EmergenceofProteinFoldFamilies throughRationalDesign Feng Ding, Nikolay V.Dokholyan* DepartmentofBiochemistryandBiophysics,UniversityofNorthCarolinaatChapelHill,ChapelHill,NorthCarolina,UnitedStatesofAmerica Diverseproteinswithsimilarstructuresaregroupedintofamiliesofhomologsandanalogs,iftheirsequencesimilarity ishigherorlower,respectively,than20%–30%.Itwassuggestedthatproteinhomologsandanalogsoriginatefroma commonancestoranddivergein theirdistinctevolutionarytimescales, emergingasaconsequenceofthephysical propertiesoftheproteinsequencespace.Althoughanumberofstudieshavedeterminedkeysignaturesofprotein familyorganization,thesequence-structurefactorsthatdifferentiatethetwoevolution-relatedproteinfamiliesremain unknown. Here, we stipulate that subtle structural changes, which appear due to accumulating mutations in the homologousfamilies,leadtodistinctpackingoftheproteincoreand,thus,novelcompositionsofcoreresidues.The latterprocessleadstotheformationofdistinctfamiliesofhomologs.Weproposethatsuchdifferentiationresultsin the formation of analogous families. To test our postulate, we developed a molecular modeling and design toolkit, Medusa,tocomputationallydesignproteinsequencesthatcorrespondtothesamefoldfamily.Wefindthatanalogous proteins emerge when a backbone structure deviates only 1–2 A? root-mean-square deviation from the original structure. For close homologs, core residues are highly conserved. However, when the overall sequence similarity drops to ;25%–30%, the composition of core residues starts to diverge, thereby forming novel families of protein homologs. This direct observation of the formation of protein homologs within a specific fold family supports our hypothesis. The conservation of amino acids in designed sequences recapitulates that of the naturally occurring sequences,therebyvalidatingourcomputationaldesignmethodology. Citation:DingF,DokholyanNV(2006)Emergenceofproteinfoldfamiliesthroughrationaldesign.PLoSComputBiol2(7):e85.DOI:10.1371/journal