From Protein Structure to Function with Bioinformatics.pdf

8 3D Motifs 193structures together. A vertex in the graph represents a pair of atoms or pseudoatoms,one from structure A and one from structure B (where “structure” could be a 3Dmotif). Only atoms with matching types are allowed to pair. Two vertices are connectedby an edge if the distance between the two atoms in A matches the distancebetween the two atoms in B, within the specified tolerance. A clique is a graph inwhich every vertex is connected to every other vertex. Thus, clique detection identifiesa set of atoms from A with internal distances completely consistent withthose among a paired set of atoms from B.● Depth-first searching. Structures are searched exhaustively for the presence of a3D motif. The search space is limited by restrictions on the atom or residue typesallowed to match, and by geometric cutoffs such as distance tolerances and anupper bound on the overall root-mean-square deviation (RMSD).● Match extension. Partial or seed matches to a 3D motif are initially identified,and then attempts are made to extend the match to the entire motif.These methods will all seek motifs in a given static structure. Recent data showthat combining a motif searching algorithm with Molecular Dynamics simulationsthat sample conformational space (see also Chapter 9) is a promising, albeit computationallyexpensive, avenue towards improving the results of the search (Glazeret al. 2008).8.2.3 Interpretation of ResultsMany web servers are available for comparing query structures to databases of 3Dmotifs (Table 8.1). What can be inferred about the function of a query when itmatches a motif? Several issues must be considered when deciding whether amatch is meaningful, and if so, what it means.What function is implied depends on how the motif was generated. If the motifrepresents a set of residues experimentally determined to be important for a particularfunction, a match suggests the query structure may perform that function.Similarly, matches to a motif based on multiple structures that perform some function(positive examples) are suggestive of that function, especially if the motif wasdesigned to exclude negative examples. What function is implied, however, dependson the criteria for membership in the positive set. For example, if the structures inthe positive set all bind adenosine but catalyze a variety of reactions, a match wouldimply adenosine binding but not necessarily adenosine deaminase activity. If thepositive set consists of representatives from a SCOP superfamily, a match wouldsuggest that the query protein also belongs to that superfamily, but would not implyanything more specific about its function.Ideally, for motif discovery the set of positive examples should be as diverseas possible while retaining the common feature, and the negative examplesshould be as similar as possible to the positive examples while lacking that feature.In practice, the positive and negative sets may not be ideal, and part or all of