Fold Designability, Distribution, and Disease 英文参考文献.docVIP

FoldDesignability,Distribution,andDisease Philip Wong1,Dmitrij Frishman1,2* 1 Institute for Bioinformatics, GSF–National Research Center for Environment and Health, Neuherberg, Germany 2 Department of Genome-Oriented Bioinformatics, TechnischeUniversita¨t Munchen,WissenschaftzentrumWeihenstephan,Freising,Germany Folddesignabilityhasbeenestimatedbythenumberoffamiliescontainedinthat fold.Here,weshowthat among orthologous proteins, sequence divergence is higher for folds with greater numbers of families. Folds with greater numbersoffamiliesalsotendtohavefamiliesthatappearmoreoftenintheproteomeandgreaterpromiscuity(the numberofunique‘‘partner’’foldsthatthefoldisfoundwithwithinthesameprotein).Wealsofindthatmanydisease- relatedproteinshavefoldswithrelativelyfewfamilies.Inparticular,anumberoftheseproteinsareassociatedwith diseases occurring at high frequency. These results suggest that family counts reflect how certain structures are distributedinnatureandisanimportantcharacteristicassociatedwithmanyhumandiseases. Citation:WongP,FrishmanD(2006)Folddesignability,distribution,anddisease.PLoSComputBiol2(5):e40.DOI:10.1371/journal.pcbi.0020040 with greater numbers of families tend to be more sequence divergent and more widespread throughout the human, Introduction Different proteins exhibit a wide range of abilities to functionallywithstandtheaffectsofenvironmentalstressor mutation. One property that has been proposed tocontrib- ute to protein functional robustness is ‘‘designability,’’ the numberofsequencesthatencodeaprotein’sstructure.Using simplelatticemodelsinwhichproteinsaremodeledaschains ofhydrophobicandhydrophilicresiduesonlattices,Lietal. [1] has shown that different proteins could have vastly different designabilities. Proteins with more designable structures (i.e., proteins that have more sequences that encode their structures) were proposed to be structurally more robust to mutation and thermal stresses [1–3]. In line with this hypothesis is the ?nd