The designability hypothesis and protein evolution
ABSTRACT The usage of protein folds in nature is known to be non-uniform: a few folds are used often, while most others are used relatively rarely. What makes one fold more successful than another? The designability explanation, which posits that successful folds have an exponentially larger number of compatible sequences, is critically reviewed, and compared with other structural and functional explanations. It is argued that designability is one component of fold fitness, but most likely not a dominant one.
- SourceAvailable from: Tong Zhou
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- "A protein's designability is defined as the total number of amino acid sequences that fold into the given structure (Li et al. 1996; Kussell 2005). Designability varies widely among structures. "
ABSTRACT: The density of contacts or the fraction of buried sites in a protein structure is thought to be related to a protein's designability, and genes encoding more designable proteins should evolve faster than other genes. Several recent studies have tested this hypothesis but have found conflicting results. Here, we investigate how a gene's evolutionary rate is affected by its protein's contact density, considering the four species Escherichia coli, Saccharomyces cerevisiae, Drosophila melanogaster, and Homo sapiens. We find for all four species that contact density correlates positively with evolutionary rate, and that these correlations do not seem to be confounded by gene expression level. The strength of this signal, however, varies widely among species. We also study the effect of contact density on domain evolution in multidomain proteins and find that a domain's contact density influences the domain's evolutionary rate. Within the same protein, a domain with higher contact density tends to evolve faster than a domain with lower contact density. Our study provides evidence that contact density can increase evolutionary rates, and that it acts similarly on the level of entire proteins and of individual protein domains.Journal of Molecular Evolution 05/2008; 66(4):395-404. DOI:10.1007/s00239-008-9094-4 · 1.86 Impact Factor
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ABSTRACT: Synopsis Most proteins are composed of structural domains that can be classified into “folds.” Domains with the same fold type share overall structural similarity. The number of amino acid sequences that encode a fold is termed the “designability” of the fold. Folds that have higher designability are thought to be more robust to stresses and mutations. Such features may also allow the fold to appear in a greater variety of contexts. Here, the authors show that proteins with folds estimated to be of higher designability are more widespread amongst proteins in human, mouse, and yeast, consistent with this hypothesis. The authors also find that many hereditary disease-associated proteins have folds estimated to be of low designability. A number of these diseases occur at a relatively high frequency. These results suggest that the estimate of designability employed reflects how certain structures are distributed in nature and is an important characteristic associated with many human diseases.PLoS Computational Biology 06/2006; 2(5):e40. DOI:10.1371/journal.pcbi.0020040 · 4.83 Impact Factor