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Protein Science (2004), 13:773-785. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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Sensitivity and selectivity in protein structure comparison

Michael L. Sierk and William R. Pearson

1 Department of Biochemistry and Molecular Genetics, University of Virginia Health System, Charlottesville, Virginia 22908, USA

(RECEIVED July 23, 2003; FINAL REVISION November 26, 2003; ACCEPTED November 28, 2003)



Abstract

Seven protein structure comparison methods and two sequence comparison programs were evaluated on their ability to detect either protein homologs or domains with the same topology (fold) as defined by the CATH structure database. The structure alignment programs Dali, Structal, Combinatorial Extension (CE), VAST, and Matras were tested along with SGM and PRIDE, which calculate a structural distance between two domains without aligning them. We also tested two sequence alignment programs, SSEARCH and PSI-BLAST. Depending upon the level of selectivity and error model, structure alignment programs can detect roughly twice as many homologous domains in CATH as sequence alignment programs. Dali finds the most homologs, 321–533 of 1120 possible true positives (28.7%–45.7%), at an error rate of 0.1 errors per query (EPQ), whereas PSI-BLAST finds 365 true positives (32.6%), regardless of the error model. At an EPQ of 1.0, Dali finds 42%–70% of possible homologs, whereas Matras finds 49%–57%; PSI-BLAST finds 36.9%. However, Dali achieves >84% coverage before the first error for half of the families tested. Dali and PSI-BLAST find 9.2% and 5.2%, respectively, of the 7056 possible topology pairs at an EPQ of 0.1 and 19.5, and 5.9% at an EPQ of 1.0. Most statistical significance estimates reported by the structural alignment programs overestimate the significance of an alignment by orders of magnitude when compared with the actual distribution of errors. These results help quantify the statistical distinction between analogous and homologous structures, and provide a benchmark for structure comparison statistics.

Keywords: structure alignment; database search; statistical significance; CATH database

Reprint requests to: William R. Pearson, Department of Biochemistry and Molecular Genetics, University of Virginia Health System, P.O. Box 800733, Charlottesville, VA 22908, USA; e-mail: wrp{at}virginia.edu; fax: (434) 924-5069.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03328504.


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