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Twilight zone of protein sequence alignments.

B Rost1

  • 1EMBL, Heidelberg, Germany.

Protein Engineering
|April 9, 1999
PubMed
Summary

This study redefines protein structural similarity detection. It clarifies that low sequence identity (20-35%) often indicates different structures, with alignment length being crucial for accuracy.

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Area of Science:

  • Bioinformatics
  • Structural Biology
  • Computational Biology

Background:

  • Protein sequence alignments are used to infer structural similarity.
  • The accuracy of this inference decreases significantly at low sequence identities (20-35%), known as the twilight zone.
  • Distinguishing true structural similarity from false positives in this zone is challenging.

Purpose of the Study:

  • To re-evaluate the threshold for distinguishing true and false positives in protein sequence alignments.
  • To redefine the reliability of sequence similarity for predicting structural similarity at low identity levels.
  • To provide guidelines for automatic database searches.

Main Methods:

  • Analysis of over a million sequence alignments between protein pairs with known structures.
  • Investigation of the impact of sequence identity and alignment length on structural similarity inference.
  • Evaluation of strategies like the 'more similar than identical' rule and the use of intermediate sequences.

Main Results:

  • A sharp increase in false negatives occurs when transitioning into the twilight zone (20-35% sequence identity).
  • Above ~30% sequence identity, 90% of pairs are homologous; below 25%, less than 10% are.
  • Alignment length is critical; high similarity over short alignments does not guarantee structural similarity.
  • The 'more similar than identical' rule and intermediate sequences improve accuracy.

Conclusions:

  • Low sequence identity (<25%) is a poor indicator of structural similarity.
  • Alignment length must be considered alongside sequence identity for reliable structural inference.
  • Findings enhance the accuracy of automated protein structure prediction and database searching.

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