Bioinformatics Advance Access published online on November 5, 2004
Bioinformatics, doi:10.1093/bioinformatics/bti125
Bioinformatics © Oxford University Press 2004; all rights reserved
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1 Department of Protein Evolution, Max-Planck-Institute for Developmental Biology, Spemannstrasse 35, D-72076 Tübingen, Germany
* To whom correspondence should be addressed.
Motivation: Protein homology detection and sequence alignment are at the basis of protein structure prediction, function prediction, and evolution. Results: We have generalized the alignment of protein sequences with a profile hidden Markov model (HMM) to the case of pairwise alignment of profile HMMs. We present a method for detecting distant homologous relationships between proteins based on this approach. The method (HHsearch) is benchmarked together with BLAST, PSI-BLAST, HMMER, and the profile-profile comparison tools PROF_SIM and COMPASS, in an all-against-all comparison of a database of 3691 protein domains from SCOP 1.63 with pairwise sequence identities below 20%. Sensitivity: When predicted secondary structure is included in the HMMs, HHsearch is able to detect between 2.7 and 4.2 times more homologs than PSI-BLAST or HMMER and between 1.44 and 1.9 times more than COMPASS or PROF_SIM for a rate of false positives of 10%. Approximately half of the improvement over the profile-profile comparison methods is attributable to the use of profile HMMs in place of simple profiles. Alignment quality: Higher sensitivity is mirrored by an increased alignment quality. HHsearch produced 1.2, 1.7, and 3.3 times more good alignments ("balanced" score > 0.3) than the next best method (COMPASS), and 1.6, 2.9, and 9.4 times more than PSI-BLAST, at the family, superfamily, and fold level. Speed: HHsearch scans a query of 200 residues against 3691 domains in 33s on an AMD64 3GHz PC. This is 10 times faster than PROF_SIM and 17 times faster than COMPASS. Availability: HHsearch can be downloaded from http://protevo.eb.tuebingen.mpg.de/download/ together with up-to-date versions of SCOP and PFAM. A web server is available at http://protevo.eb.tuebingen.mpg.de/toolkit/index.php?view=hhpred.
Revised October 18, 2004
Accepted November 2, 2004
Article
Protein homology detection by HMM-HMM comparison
Johannes Söding, E-mail: johannes.soeding{at}tuebingen.mpg.de
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