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The meaning of alignment: lessons from structural diversity.

Pirovano W, Feenstra KA, Heringa J - BMC Bioinformatics (2008)

Bottom Line: However, the available techniques do not fully consider the implications of protein structural diversity and typically generate a single alignment between sequences.We show that structural diversity has a significant effect on structural alignment.A comprehensive treatment of ambiguous alignment regions is crucial for further development of structural alignment applications and for the representation of alignments in general.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Integrative Bioinformatics VU (IBIVU), VU University Amsterdam, De Boelelaan 1081A, 1081HV Amsterdam, the Netherlands. pirovano@few.vu.nl

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.

Conclusion: 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.

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Dealing with structural flexibility: a single insertion (5', left) can lead to ambiguity in the pairwise residue alignment between the loops (right). Therefore, a simple one-to-one functional equivalence between residues from different proteins may not exist.
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Figure 1: Dealing with structural flexibility: a single insertion (5', left) can lead to ambiguity in the pairwise residue alignment between the loops (right). Therefore, a simple one-to-one functional equivalence between residues from different proteins may not exist.

Mentions: Recent structural alignment methods have started to place emphasis on dealing with structural flexibility, such as FATCAT [19], MultiProt [20], MATT [21] and RAPIDO [22]. This may increase the consistency of alignments produced by each of these methods, but does not address the intrinsic ambiguity arising from structural divergence. The fundamental issue is whether a one-to-one equivalence exists between residues from different proteins that could be expressed as one definite alignment between sequences [18]. This is illustrated in Figure 1, where we show that a single insertion can lead to ambiguity in the functional correspondence between most residues in the loop.


The meaning of alignment: lessons from structural diversity.

Pirovano W, Feenstra KA, Heringa J - BMC Bioinformatics (2008)

Dealing with structural flexibility: a single insertion (5', left) can lead to ambiguity in the pairwise residue alignment between the loops (right). Therefore, a simple one-to-one functional equivalence between residues from different proteins may not exist.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2630330&req=5

Figure 1: Dealing with structural flexibility: a single insertion (5', left) can lead to ambiguity in the pairwise residue alignment between the loops (right). Therefore, a simple one-to-one functional equivalence between residues from different proteins may not exist.
Mentions: Recent structural alignment methods have started to place emphasis on dealing with structural flexibility, such as FATCAT [19], MultiProt [20], MATT [21] and RAPIDO [22]. This may increase the consistency of alignments produced by each of these methods, but does not address the intrinsic ambiguity arising from structural divergence. The fundamental issue is whether a one-to-one equivalence exists between residues from different proteins that could be expressed as one definite alignment between sequences [18]. This is illustrated in Figure 1, where we show that a single insertion can lead to ambiguity in the functional correspondence between most residues in the loop.

Bottom Line: However, the available techniques do not fully consider the implications of protein structural diversity and typically generate a single alignment between sequences.We show that structural diversity has a significant effect on structural alignment.A comprehensive treatment of ambiguous alignment regions is crucial for further development of structural alignment applications and for the representation of alignments in general.

View Article: PubMed Central - HTML - PubMed

Affiliation: Centre for Integrative Bioinformatics VU (IBIVU), VU University Amsterdam, De Boelelaan 1081A, 1081HV Amsterdam, the Netherlands. pirovano@few.vu.nl

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.

Conclusion: 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.

Show MeSH