Nucleic Acids Research Advance Access published March 16, 2007 Consensus sequences improve.pdf

Nucleic Acids Research, 2007, 1–9 doi:10.1093/nar/gkm107 Consensus sequences improve PSI-BLAST through mimicking profile–profile alignments Dariusz Przybylski1,2,* and Burkhard Rost1,2,3 1Department of Biochemistry and Molecular Biophysics, Columbia University, 630 West 168th Street, New York, NY 10032, USA, 2Columbia University Center for Computational Biology and Bioinformatics (C2B2), 1130St. Nicholas Ave. Rm. 801, New York, NY 10032, USA and 3NorthEast Structural Genomics Consortium (NESG), Columbia University, 1130St. Nicholas Ave. Rm. 802, New York, NY 10032, USA Received December 20, 2006; Revised February 5, 2007; Accepted February 6, 2007 ABSTRACT Sequence alignments may be the most fundamental computational resource for molecular biology. The best methods that identify sequence relatedness through profile–profile comparisons are much slower and more complex than sequence–sequence and sequence–profile comparisons such as, respectively, BLAST and PSI-BLAST. Families of related genes and gene products (proteins) can be represented by consensus sequences that list the nucleic/amino acid most frequent at each sequence position in that family. Here, we propose a novel approach for consensus-sequence-based compar- isons. This approach improved searches and align- ments as a standard add-on to PSI-BLAST without any changes of code. Improvements were particu- larly significant for more difficult tasks such as the identification of distant structural relations between proteins and their corresponding alignments. Despite the fact that the improvements were higher for more divergent relations, they were con- sistent even at high accuracy/low error rates for non-trivially related proteins. The improvements were very easy to achieve; no parameter used by PSI-BLAST was altered and no single line of code changed. Furthermore, the consensus sequence add-on required relatively little additional CPU time. We discuss how advanced users of PSI- BLAST can immediately benefit fr