Twilight zone of protein sequence alignments
- 31 January 1999
- journal article
- research article
- Published by Oxford University Press (OUP) in Protein Engineering, Design and Selection
- Vol. 12 (2), 85-94
- https://doi.org/10.1093/protein/12.2.85
Abstract
Sequence alignments unambiguously distinguish between protein pairs of similar and non-similar structure when the pairwise sequence identity is high (>40% for long alignments). The signal gets blurred in the twilight zone of 20-35% sequence identity. Here, more than a million sequence alignments were analysed between protein pairs of known structures to re-define a line distinguishing between true and false positives for low levels of similarity. Four results stood out. (i) The transition from the safe zone of sequence alignment into the twilight zone is described by an explosion of false negatives. More than 95% of all pairs detected in the twilight zone had different structures. More precisely, above a cut-off roughly corresponding to 30% sequence identity, 90% of the pairs were homologous; below 25% less than 10% were. (ii) Whether or not sequence homology implied structural identity depended crucially on the alignment length. For example, if 10 residues were similar in an alignment of length 16 (>60 %), structural similarity could not be inferred. (iii) The 'more similar than identical' rule (discarding all pairs for which percentage similarity was lower than percentage identity) reduced false positives significantly. (iv) Using intermediate sequences for finding links between more distant families was almost as successful: pairs were predicted to be homologous when the respective sequence families had proteins in common. All findings are applicable to automatic database searches.This publication has 60 references indexed in Scilit:
- Assessing sequence comparison methods with reliable structurally identified distant evolutionary relationshipsProceedings of the National Academy of Sciences of the United States of America, 1998
- Do aligned sequences share the same fold?Journal of Molecular Biology, 1997
- Gapped BLAST and PSI-BLAST: a new generation of protein database search programsNucleic Acids Research, 1997
- The SWISS-PROT protein sequence data bank and its supplement TrEMBLNucleic Acids Research, 1997
- [37] Understanding protein structure: Using scop for fold interpretationMethods in Enzymology, 1996
- [27] Local alignment statisticsMethods in Enzymology, 1996
- Statistics of sequence-structure threadingCurrent Opinion in Structural Biology, 1995
- Common spatial arrangements of backbone fragments in homologous and non-homologous proteinsJournal of Molecular Biology, 1992
- Basic local alignment search toolJournal of Molecular Biology, 1990
- The protein data bank: A computer-based archival file for macromolecular structuresJournal of Molecular Biology, 1977