title: Evolutionary inaccuracy of pairwise structural alignments.
abstract: BACKGROUND
  Structural alignment methods are widely used to generate gold standard alignments for improving multiple sequence alignments and transferring functional annotations, as well as for assigning structural distances between proteins. However, the correctness of the alignments generated by these methods is difficult to assess objectively since little is known about the exact evolutionary history of most proteins. Since homology is an equivalence relation, an upper bound on alignment quality can be found by assessing the consistency of alignments. Measuring the consistency of current methods of structure alignment and determining the causes of inconsistencies can, therefore, provide information on the quality of current methods and suggest possibilities for further improvement.
  
  
  RESULTS
  We analyze the self-consistency of seven widely-used structural alignment methods (SAP, TM-align, Fr-TM-align, MAMMOTH, DALI, CE and FATCAT) on a diverse, non-redundant set of 1863 domains from the SCOP database and demonstrate that even for relatively similar proteins the degree of inconsistency of the alignments on a residue level is high (30%). We further show that levels of consistency vary substantially between methods, with two methods (SAP and Fr-TM-align) producing more consistent alignments than the rest. Inconsistency is found to be higher near gaps and for proteins of low structural complexity, as well as for helices. The ability of the methods to identify good structural alignments is also assessed using geometric measures, for which FATCAT (flexible mode) is found to be the best performer despite being highly inconsistent. We conclude that there is substantial scope for improving the consistency of structural alignment methods.
  
  
  BACKGROUND
  msadows@nimr.mrc.ac.uk
  
  
  BACKGROUND
  Supplementary data are available at Bioinformatics online.
authors.affiliation: Division of Mathematical Biology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, UK.
authors.forename: M I
authors.initials: MI
authors.lastname: Sadowski
authors.forename: W R
authors.initials: WR
authors.lastname: Taylor
mesh_terms: D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*; D016415:Sequence Alignment / Q000379:methods*; D020539:Sequence Analysis, Protein / Q000379:methods*; D040681:Structural Homology, Protein
chemical_list: D011506:Proteins