Abstract
BackgroundStructural genomics approaches, particularly those solving the 3D structures of many proteins with unknown functions, have increased the desire for structure-based function predictions. However, prediction of enzyme function is difficult because one member of a superfamily may catalyze a different reaction than other members, whereas members of different superfamilies can catalyze the same reaction. In addition, conformational changes, mutations or the absence of a particular catalytic residue can prevent inference of the mechanism by which catalytic residues stabilize and promote the elementary reaction. A major hurdle for alignment-based methods for prediction of function is the absence (despite its importance) of a measure of similarity of the physicochemical properties of catalytic sites. To solve this problem, the physicochemical features radially distributed around catalytic sites should be considered in addition to structural and sequence similarities.ResultsWe showed that radial distribution functions (RDFs), which are associated with the local structural and physicochemical properties of catalytic active sites, are capable of clustering oxidoreductases and transferases by function. The catalytic sites of these enzymes were also characterized using the RDFs. The RDFs provided a measure of the similarity among the catalytic sites, detecting conformational changes caused by mutation of catalytic residues. Furthermore, the RDFs reinforced the classification of enzyme functions based on conventional sequence and structural alignments.ConclusionsOur results demonstrate that the application of RDFs provides advantages in the functional classification of enzymes by providing information about catalytic sites.
Highlights
Structural genomics approaches, those solving the 3D structures of many proteins with unknown functions, have increased the desire for structure-based function predictions
We examine the structures of oxidoreductases and transferases using radial distribution functions (RDFs) that encode radially distributed properties of active sites centered around the reacting points of bound ligands
The degenerated total charge of the catalytic residues corresponded to the RDF with a range from 0 to 5 Å for both enzymes (Figure 1C, D)
Summary
Characteristic physicochemical pattern of active sites To examine how catalytic residues contribute to the radially distributed properties of active sites, we decomposed the RDF into the total charge for each residue. The conformation of the catalytic site in the CCPR_YEAST protein is not altered by the mutation included in this analysis (PDB code: 3ccp) [25] These results show that the Euclidean distance between the RDFs reflects the conformational changes in the active sites. In oxidoreductases, these values, ranging from 0.729 to 0.746, represented higher performance compared to the values obtained using sequence and structural alignments (Table 6). The AUC values of 0.800 and 0.790 for the datasets with pairwise identities below 15% represented higher performance compared to the values obtained using sequence and structural alignments (Table 7) Of the predicted EC numbers, the rates of validated prediction that the EC number is compatible with the bound ligands were 59% of the ETA predictions and 72% of the SOM predictions, suggesting the SOM predictions provide a clue to annotate these functions (Table 9)
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