Motivation: A typical PSI-BLAST search consists of iterative scanning and alignment of a large sequence database during which a scoring profile is progressively built and refined. Such a profile can also be stored and used to search against a different database of sequences. Using it to search against a database of consensus rather than native sequences is a simple add-on that boosts performance surprisingly well. The improvement comes at a price: we hypothesized that random alignment score statistics would differ between native and consensus sequences. Thus PSI-BLAST-based profile searches against consensus sequences might incorrectly estimate statistical significance of alignment scores. In addition, iterative searches against consensus databases may fail. Here, we addressed these challenges in an attempt to harness the full power of the combination of PSI-BLAST and consensus sequences.
Results: We studied alignment score statistics for various types of consensus sequences. In general, the score distribution parameters of profile-based consensus sequence alignments differed significantly from those derived for the native sequences. PSI-BLAST partially compensated for the parameter variation. We have identified a protocol for building specialized consensus sequences that significantly improved search sensitivity and preserved score distribution parameters. As a result, PSI-BLAST profiles can be used to search specialized consensus sequences without sacrificing estimates of statistical significance. We also provided results indicating that iterative PSI-BLAST searches against consensus sequences could work very well. Overall, we showed how a very popular and effective method could be used to identify significantly more relevant similarities among protein sequences.
Availability: http://www.rostlab.org/services/consensus/.