title: The meaning of alignment: lessons from structural diversity.
abstract: BACKGROUND
  Protein structural alignment provides a fundamental basis for deriving principles of functional and evolutionary relationships. It is routinely used for structural classification and functional characterization of proteins and for the construction of sequence alignment benchmarks. However, the available techniques do not fully consider the implications of protein structural diversity and typically generate a single alignment between sequences.
  
  
  RESULTS
  We have taken alternative protein crystal structures and generated simulation snapshots to explicitly investigate the impact of structural changes on the alignments. We show that structural diversity has a significant effect on structural alignment. Moreover, we observe alignment inconsistencies even for modest spatial divergence, implying that the biological interpretation of alignments is less straightforward than commonly assumed. A salient example is the GroES 'mobile loop' where sub-Angstrom variations give rise to contradictory sequence alignments.
  
  
  CONCLUSIONS
  A comprehensive treatment of ambiguous alignment regions is crucial for further development of structural alignment applications and for the representation of alignments in general. For this purpose we have developed an on-line database containing our data and new ways of visualizing alignment inconsistencies, which can be found at http://www.ibi.vu.nl/databases/stralivari.
authors.affiliation: Centre for Integrative Bioinformatics VU (IBIVU), VU University Amsterdam, De Boelelaan 1081A, 1081HV Amsterdam, the Netherlands. pirovano@few.vu.nl
authors.forename: Walter
authors.initials: W
authors.lastname: Pirovano
authors.forename: K Anton
authors.initials: KA
authors.lastname: Feenstra
authors.forename: Jaap
authors.initials: J
authors.lastname: Heringa
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D003460:Crystallization; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D011506:Proteins / Q000737:chemistry; D016415:Sequence Alignment / Q000379:methods*; D017386:Sequence Homology, Amino Acid; D012984:Software
chemical_list: D011506:Proteins