title: Improving the accuracy of PSI-BLAST protein database searches with composition-based statistics and other refinements.
abstract: PSI-BLAST is an iterative program to search a database for proteins with distant similarity to a query sequence. We investigated over a dozen modifications to the methods used in PSI-BLAST, with the goal of improving accuracy in finding true positive matches. To evaluate performance we used a set of 103 queries for which the true positives in yeast had been annotated by human experts, and a popular measure of retrieval accuracy (ROC) that can be normalized to take on values between 0 (worst) and 1 (best). The modifications we consider novel improve the ROC score from 0.758 +/- 0.005 to 0.895 +/- 0.003. This does not include the benefits from four modifications we included in the 'baseline' version, even though they were not implemented in PSI-BLAST version 2.0. The improvement in accuracy was confirmed on a small second test set. This test involved analyzing three protein families with curated lists of true positives from the non-redundant protein database. The modification that accounts for the majority of the improvement is the use, for each database sequence, of a position-specific scoring system tuned to that sequence's amino acid composition. The use of composition-based statistics is particularly beneficial for large-scale automated applications of PSI-BLAST.
authors.affiliation: National Center for Biotechnology Information, National Institutes of Health, 8600 Rockville Pike, Bethesda, MD 20894, USA. schaffer@helix.nih.gov
authors.forename: A A
authors.initials: AA
authors.lastname: Schäffer
authors.forename: L
authors.initials: L
authors.lastname: Aravind
authors.forename: T L
authors.initials: TL
authors.lastname: Madden
authors.forename: S
authors.initials: S
authors.lastname: Shavirin
authors.forename: J L
authors.initials: JL
authors.lastname: Spouge
authors.forename: Y I
authors.initials: YI
authors.lastname: Wolf
authors.forename: E V
authors.initials: EV
authors.lastname: Koonin
authors.forename: S F
authors.initials: SF
authors.lastname: Altschul
mesh_terms: D000465:Algorithms; D000596:Amino Acids / Q000235:genetics; D000818:Animals; D019295:Computational Biology / Q000379:methods / Q000706:statistics & numerical data; D016208:Databases, Factual; D006801:Humans; D016247:Information Storage and Retrieval; D011506:Proteins / Q000235:genetics*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016415:Sequence Alignment / Q000379:methods*; D012984:Software
chemical_list: D000596:Amino Acids; D011506:Proteins