Inferring functional relationships of proteins from local sequence and spatial surface patterns.

We describe a novel approach for inferring functional relationship of proteins by detecting sequence and spatial patterns of protein surfaces. Well-formed concave surface regions in the form of pockets and voids are examined to identify similarity relationship that might be directly related to protein function. We first exhaustively identify and measure analytically all 910,379 surface pockets and interior voids on 12,177 protein structures from the Protein Data Bank. The similarity of patterns of residues forming pockets and voids are then assessed in sequence, in spatial arrangement, and in orientational arrangement. Statistical significance in the form of E and p-values is then estimated for each of the three types of similarity measurements. Our method is fully automated without human intervention and can be used without input of query patterns. It does not assume any prior knowledge of functional residues of a protein, and can detect similarity based on surface patterns small and large. It also tolerates, to some extent, conformational flexibility of functional sites. We show with examples that this method can detect functional relationship with specificity for members of the same protein family and superfamily, as well as remotely related functional surfaces from proteins of different fold structures. We envision that this method can be used for discovering novel functional relationship of protein surfaces, for functional annotation of protein structures with unknown biological roles, and for further inquiries on evolutionary origins of structural elements important for protein function.