From Protein Structure to Function with Bioinformatics.pdf

190 E.C. Meng et al.not previously seen within that superfamily. Like functional classifications,structural classifications do not provide direct information about the specificstructural features associated with a function.8.1.2 Three-Dimensional Motifs: Definition and ScopeThree-dimensional motifs are spatial patterns of points based on a few residues(generally under a dozen) associated with some protein function or classificationof interest. They are sometimes called active site templates, since the residuesmay contribute to a binding or catalytic pocket, or structural templates. Thepositions of one or a few atoms per residue are used, and the points are labelledwith additional information, such as atom and residue type, used in matching.Three-dimensional motifs are local and discontinuous; the residues are clusteredin space but not necessarily in sequence, and sequence order is usually disregardedduring matching. They do not describe peptide chain conformations orwhole domains.8.2 Overview of Methods8.2.1 Motif DiscoveryThree-dimensional motifs are identified by mining structures for patterns of atomsor residues deemed functionally relevant. Discovery methods can be grouped intoa few general categories:1. Literature. Residues important for a particular function are gleaned from the literatureand other sources of experimental data. This “expert knowledge”approach, while capable of producing high-quality motifs for which the constituentresidues have been experimentally shown to be functionally important, istime-intensive and resistant to automation.2. Undirected mining. A sample of all structures is searched for statistically anomalouspatterns, without presupposition of their functional roles.3. Individual structures. Structures are considered one by one. Sets of residues neara bound ligand or named in PDB SITE records are simply taken as a motif.There is no attempt to group structures or to generate consensus patterns.4. Positive examples. Motifs are identified by comparisons among true positivestructures (proteins that perform the function of interest or that belong to thestructural classification of interest). Other structures are not considered.5. Positive and negative examples. Motifs are generated based on their ability toidentify true positive structures and to exclude other structures.