Evolutionary and structural feedback on selection of sequences for comparative analysis of proteins.
It has been noted that slowly evolving protein residues have two properties: (a) they tend to cluster in the native fold, and (b) they delineate functional surfaces-parts of the surface through which the protein interacts with other proteins or small ligands. Herein, we demonstrate that the two are coupled sufficiently strongly that one effect, when observed, statistically implies the other. Detection of both can be accomplished in multiple sequence alignment related methods by the careful selection of relevant sequences. For the demonstration, we use two sets of protein families: a small set of diverse proteins with diverse functional surfaces, and a large set of homodimerizing enzymes. A practical outcome of our considerations is a simple prescriptive rule for the selection of homologous sequences for the comparative analysis of proteins: in order to optimize the detection of (potentially unknown) functional surfaces, it is sufficient to select sequences in such a way that the residues observed at any level of evolutionary divergence, as implied by the alignment, cluster on the folded protein.
Mihalek
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Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA. imihalek@bcm.tmc.edu
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Lichtarge
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D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002950:Citrate (si)-Synthase / Q000737:chemistry; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods*; D030562:Databases, Protein; D019281:Dimerization; D019143:Evolution, Molecular; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015233:Models, Statistical; D008962:Models, Theoretical; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D010802:Phylogeny; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D025941:Protein Interaction Mapping; D011506:Proteins / Q000737:chemistry*; D040901:Proteomics / Q000379:methods*; D016415:Sequence Alignment
D008024:Ligands; D011506:Proteins; D002950:Citrate (si)-Synthase