Functional annotation by sequence-weighted structure alignments: statistical analysis and case studies from the Protein 3000 structural genomics project in Japan.
A method to functionally annotate structural genomics targets, based on a novel structural alignment scoring function, is proposed. In the proposed score, position-specific scoring matrices are used to weight structurally aligned residue pairs to highlight evolutionarily conserved motifs. The functional form of the score is first optimized for discriminating domains belonging to the same Pfam family from domains belonging to different families but the same CATH or SCOP superfamily. In the optimization stage, we consider four standard weighting functions as well as our own, the "maximum substitution probability," and combinations of these functions. The optimized score achieves an area of 0.87 under the receiver-operating characteristic curve with respect to identifying Pfam families within a sequence-unique benchmark set of domain pairs. Confidence measures are then derived from the benchmark distribution of true-positive scores. The alignment method is next applied to the task of functionally annotating 230 query proteins released to the public as part of the Protein 3000 structural genomics project in Japan. Of these queries, 78 were found to align to templates with the same Pfam family as the query or had sequence identities > or = 30%. Another 49 queries were found to match more distantly related templates. Within this group, the template predicted by our method to be the closest functional relative was often not the most structurally similar. Several nontrivial cases are discussed in detail. Finally, 103 queries matched templates at the fold level, but not the family or superfamily level, and remain functionally uncharacterized.
Standley
Daron M
DM
Research Center for Structural and Functional Proteomics, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan. standley@protein.osaka-u.ac.jp
Toh
Hiroyuki
H
Nakamura
Haruki
H
D020816:Amino Acid Motifs; D000818:Animals; D019295:Computational Biology / Q000379:methods*; D017124:Conserved Sequence; D023281:Genomics; D006801:Humans; D007564:Japan; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000502:physiology; D016415:Sequence Alignment / Q000379:methods*
D011506:Proteins