Analysis of protein structures reveals regions of rare backbone conformation at functional sites

Regions of rare conformation were located in 300 protein crystal structures representing seven major protein folds. A distance matrix algorithm was used to search rapidly for 9-residue fragments of rare backbone conformation using a comparison to a relational database of encoded fragments derived from the database of nonredundant structures. Rare fragments were found in 61% of the analyzed protein structures. Detailed analysis was performed for 78 proteins of different folds. The rare fragments were located near functional sites in 72% of the protein structures. The rare fragments often formed parts of ligand-binding sites (59%), protein-protein interfaces (8%), and domain-domain contacts (5%). Of the remaining structures, 5% had a high average B-factor or high local B-factors. Statistical analysis suggests that the association between ligands and rare regions does not occur by chance alone. The present study is likely to underestimate the number of functional sites, because not all analyzed protein structures contained a ligand. The results suggest that rapid searches for regions with rare local backbone conformations can assist in prediction of functional sites in novel proteins.