Protein homology detection by HMM-HMM comparison

Bioinformatics. 2005 Apr 1;21(7):951-60. doi: 10.1093/bioinformatics/bti125. Epub 2004 Nov 5.


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 the 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, respectively.Speed: HHsearch scans a query of 200 residues against 3691 domains in 33 s on an AMD64 2GHz PC. This is 10 times faster than PROF_SIM and 17 times faster than COMPASS.

Publication types

  • Comparative Study
  • Evaluation Study
  • Validation Study

MeSH terms

  • Algorithms*
  • Amino Acid Sequence
  • Artificial Intelligence*
  • Computer Simulation
  • Markov Chains
  • Models, Chemical
  • Models, Statistical
  • Molecular Sequence Data
  • Proteins / analysis
  • Proteins / chemistry*
  • Sequence Alignment / methods*
  • Sequence Analysis, Protein / methods*
  • Sequence Homology, Amino Acid
  • Software


  • Proteins