Accuracy of structure-based sequence alignment of automatic methods.
BACKGROUND
Accurate sequence alignments are essential for homology searches and for building three-dimensional structural models of proteins. Since structure is better conserved than sequence, structure alignments have been used to guide sequence alignments and are commonly used as the gold standard for sequence alignment evaluation. Nonetheless, as far as we know, there is no report of a systematic evaluation of pairwise structure alignment programs in terms of the sequence alignment accuracy.


RESULTS
In this study, we evaluate CE, DaliLite, FAST, LOCK2, MATRAS, SHEBA and VAST in terms of the accuracy of the sequence alignments they produce, using sequence alignments from NCBI's human-curated Conserved Domain Database (CDD) as the standard of truth. We find that 4 to 9% of the residues on average are either not aligned or aligned with more than 8 residues of shift error and that an additional 6 to 14% of residues on average are misaligned by 1-8 residues, depending on the program and the data set used. The fraction of correctly aligned residues generally decreases as the sequence similarity decreases or as the RMSD between the C alpha positions of the two structures increases. It varies significantly across CDD superfamilies whether shift error is allowed or not. Also, alignments with different shift errors occur between proteins within the same CDD superfamily, leading to inconsistent alignments between superfamily members. In general, residue pairs that are more than 3.0 A apart in the reference alignment are heavily (>or= 25% on average) misaligned in the test alignments. In addition, each method shows a different pattern of relative weaknesses for different SCOP classes. CE gives relatively poor results for beta-sheet-containing structures (all-beta, alpha/beta, and alpha+beta classes), DaliLite for "others" class where all but the major four classes are combined, and LOCK2 and VAST for all-beta and "others" classes.


CONCLUSIONS
When the sequence similarity is low, structure-based methods produce better sequence alignments than by using sequence similarities alone. However, current structure-based methods still mis-align 11-19% of the conserved core residues when compared to the human-curated CDD alignments. The alignment quality of each program depends on the protein structural type and similarity, with DaliLite showing the most agreement with CDD on average.
Kim
Changhoon
C
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute National Institutes of Health, Bethesda, Maryland, USA. kimchan@mail.nih.gov
Lee
Byungkook
B
D000465:Algorithms; D000595:Amino Acid Sequence; D001185:Artificial Intelligence; D008969:Molecular Sequence Data; D010363:Pattern Recognition, Automated / Q000379:methods*; D011506:Proteins / Q000737:chemistry*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016415:Sequence Alignment / Q000379:methods*; D020539:Sequence Analysis, Protein / Q000379:methods*; D017386:Sequence Homology, Amino Acid; D012984:Software; D012986:Software Validation
D011506:Proteins