From Protein Structure to Function with Bioinformatics.pdf

204 E.C. Meng et al.are compared, pairs of similar triangles are identified first, and then consistent setsof pairs, or patches. Patches are refined by pruning pairs of chemical groups thatsuperimpose relatively poorly or differ significantly in their degree of burial.The Protemot web server (Chang et al. 2006) (Table 8.1) compares a structureto a database of binding site motifs, defined as residues with at least one atomwithin 4.5 Å of a ligand. Redundant chains at 60% sequence identity and sites bindingbiologically uninteresting ligands were excluded from the database. It is possibleto search all motifs or only those from enzymes or particular classes of enzymes.A query structure is filtered down to only the alpha-carbons near a cavity, labelledby residue type. This information is hashed and compared to hashes for databaseentries. The user specifies a similarity threshold for residue pairing. The 100 bestrough matches are then refined to include more residues, and only matches withsimilar cavity directionalities and RMSD values within 1.5 Å are returned. A matchis shown graphically, but there is no list of which residues were paired, only thePDB codes of the hits.The pdbFun web server (Ausiello et al. 2005b) (Table 8.1) allows probe and targetsets of residues to be compared using Query3D (Ausiello et al. 2005a)(described in the previous section). Residues can be specified individually by hand,or predefined sets or their Boolean combinations can be used. One type of predefinedset is a binding site, the residues within 3.5 Å of a ligand. Active sites asdefined in the CATRES database (Bartlett et al. 2002) from literature informationare also available. The probe set can only include residues from one chain, but thetarget set can contain up to the entire pdbFun database (∼50,000 chains).Specification of the probe and target residue sets is very flexible, but can be confusing.To enable fast searching, the RMSD cutoff is very stringent and cannot beadjusted. However, Query3D can be obtained from the authors for local use (onUnix platforms). In this implementation, desired cutoff settings can be defined bythe user (Ausiello et al. 2005a).8.3.2.4 Positive ExamplesLocal structural features shared among proteins that perform a given function orthat belong to a particular structural classification may be taken as a 3D motif. Thisapproach uses multiple positive examples to determine which atoms or residues toinclude in a motif, although the motif coordinates may be taken from a single structurerather than averaged. Negative examples are not considered during motif generation,although they are often used in evaluation.Some ligand-centric studies used a rigid part of the ligand to superimpose the bindingsites. For example, adenine was superimposed to compare different adeninemononucleotide-binding sites. One study involved all-by-all comparisons of the 121adenine mononucleotide complexes then available, 38 after redundancy filtering(Kobayashi and Go 1997). For each pair of structures, the number of correspondingatom pairs (based on element and proximity) near adenine and how well they superimposedwere evaluated. A high similarity was found between structures of different