Sequence-structure specificity--how does an inverse folding approach work?

The inverse folding approach is a powerful tool in protein structure prediction when the native state of a sequence adopts one of the known protein folds. This is because some proteins show strong sequence-structure specificity in inverse folding experiments that allow gaps and insertions in the sequence-structure alignment. In those cases when structures similar to their native folds are included in the structure database, the z-scores (which measure the sequence-structure specificity) of these folds are well separated from those of other alternative structures. In this paper, we seek to understand the origin of this sequence-structure specificity and to identify how the specificity arises on passing from a short peptide chain to the entire protein sequence. To accomplish this objective, a simplified version of inverse folding, gapless inverse folding, is performed using sequence fragments of different sizes from 53 proteins. The results indicate that usually a significant portion of the entire protein sequence is necessary to show sequence-structure specificity, but there are regions in the sequence that begin to show this specificity at relatively short fragment size (15-20 residues). An island picture, in which the regions in the sequence that recognize their own native structure grow from some seed fragments, is observed as the fragment size increases. Usually, more similar structures to the native states are found in the top-scoring structural fragments in these high-specificity regions.