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Detection of homologous proteins by an intermediate sequence search

¹ Laboratory of Molecular Biophysics, Pels Family Center for Biochemistry and Structural Biology, The Rockefeller University, New York, New York 10021, USA
² Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry, and California Institute for Quantitative Biomedical Research, University of California at San Francisco, San Francisco, California 94143, USA

Reprint requests to: Andrej Sali, Mission Bay Genentech Hall, Ste. N472D, 600 16th St., University of California at San Francisco, San Francisco, CA 94143, USA; e-mail: sali{at}salilab.org; fax: (415) 514-4231.

We developed a variant of the intermediate sequence search method (ISS_new) for detection and alignment of weakly similar pairs of protein sequences. ISS_new relates two query sequences by an intermediate sequence that is potentially homologous to both queries. The improvement was achieved by a more robust overlap score for a match between the queries through an intermediate. The approach was benchmarked on a data set of 2369 sequences of known structure with insignificant sequence similarity to each other (BLAST E-value larger than 0.001); 2050 of these sequences had a related structure in the set. ISS_new performed significantly better than both PSI-BLAST and a previously described intermediate sequence search method. PSI-BLAST could not detect correct homologs for 1619 of the 2369 sequences. In contrast, ISS_new assigned a correct homolog as the top hit for 121 of these 1619 sequences, while incorrectly assigning homologs for only nine targets; it did not assign homologs for the remainder of the sequences. By estimate, ISS_new may be able to assign the folds of domains in ~29,000 of the ~500,000 sequences unassigned by PSI-BLAST, with 90% specificity (1 - false positives fraction). In addition, we show that the 15 alignments with the most significant BLAST E-values include the nearly best alignments constructed by ISS_new.

Keywords: protein homology; protein evolution; sequence alignment; comparative protein structure modeling; fold assignment

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