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Large-scale comparison of protein sequence alignment algorithms with structure alignments.

J M Sauder1, J W Arthur, R L Dunbrack

  • 1Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

Proteins
|May 17, 2000
PubMed
Summary
This summary is machine-generated.

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Assessing sequence alignment methods like BLAST and PSI-BLAST for remote homology detection reveals their limitations at low sequence identity. Intermediate sequence search (ISS) shows promise for improving alignment accuracy and length in protein structure prediction.

Area of Science:

  • Bioinformatics
  • Computational Biology
  • Structural Bioinformatics

Background:

  • Sequence alignment programs (BLAST, PSI-BLAST) are crucial for detecting remote protein homologies, aiding in fold assignment and comparative modeling.
  • The accuracy of these sequence alignment methods at low sequence identities (<25%) remains largely unquantified.
  • Structural alignment programs like CE provide a benchmark for evaluating sequence alignment quality.

Purpose of the Study:

  • To evaluate the performance of standard sequence alignment methods (BLAST, PSI-BLAST, CLUSTALW) and intermediate sequence search (ISS) at low sequence identities.
  • To compare sequence-based alignments against structure-based alignments derived from the CE and FSSP databases.
  • To determine the utility of intermediate sequences for improving fold assignment and comparative modeling.

Related Experiment Videos

Main Methods:

  • Derived sequence alignments from SCOP database superfamily and family relationships using the CE structure alignment program.
  • Compared alignments from BLAST, PSI-BLAST, CLUSTALW, and ISS against CE structural alignments.
  • Utilized PSI-BLAST for iterative searches against the nonredundant (nr) sequence database to identify linked sequences within SCOP superfamilies.

Main Results:

  • CLUSTALW alignments showed poor performance (<25% identity) compared to CE structural alignments.
  • PSI-BLAST improved alignment accuracy and length over BLAST, correctly aligning 40% of residues at 10-15% sequence identity, compared to BLAST's 28%.
  • Intermediate sequence search (ISS) yielded longer alignments than PSI-BLAST alone, with 46% residue accuracy at 10-15% identity, approaching the 75% accuracy of structure-based alignments (CE/FSSP).

Conclusions:

  • Standard sequence alignment methods exhibit significant limitations in accuracy at low sequence identities.
  • Intermediate sequence search (ISS) offers a substantial improvement over standalone PSI-BLAST for generating longer and more accurate alignments.
  • Intermediate sequences are valuable for enhancing both fold assignment and the completeness of sequence alignments for comparative modeling.