Quantifying the Similarities within Fold Space

We have used GRATH, a graph-based structure comparison algorithm, to map the similarities between the different folds observed in the CATH domain structure database. Statistical analysis of the distributions of the fold similarities has allowed us to assess the significance for any similarity. Therefore we have examined whether it is best to represent folds as discrete entities or whether, in fact, a more accurate model would be a continuum wherein folds overlap via common motifs. To do this we have introduced a new statistical measure of fold similarity, termed gregariousness. For a particular fold, gregariousness measures how many other folds have a significant structural overlap with that fold, typically comprising 40% or more of the larger structure. Gregarious folds often contain commonly occurring super-secondary structural motifs, such as β-meanders, greek keys, α–β plait motifs or α-hairpins, which are matching similar motifs in other folds. Apart from one example, all the most gregarious folds matching 20% or more of the other folds in the database, are α–β proteins. They also occur in highly populated architectural regions of fold space, adopting sandwich-like arrangements containing two or more layers of α-helices and β-strands.