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Open Access Research

Quod erat demonstrandum? The mystery of experimental validation of apparently erroneous computational analyses of protein sequences

Lakshminarayan M Iyer1, L Aravind1, Peer Bork2, Kay Hofmann3, Arcady R Mushegian4, Igor B Zhulin5 and Eugene V Koonin1*

Author Affiliations

1 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA

2 EMBL, Biocomputing, Meyerhofstrasse 1, 69117 Heidelberg, Germany

3 MEMOREC Stoffel GmbH, Köln D-50829, Germany

4 Stowers Institute for Medical Research, 1000 E 50th Street, Kansas City, MO 64410, USA

5 School of Biology, Georgia Institute of Technology, Atlanta, GA 30332, USA

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Genome Biology 2001, 2:research0051-research0051.11  doi:10.1186/gb-2001-2-12-research0051

Published: 13 November 2001

Abstract

Background

Computational predictions are critical for directing the experimental study of protein functions. Therefore it is paradoxical when an apparently erroneous computational prediction seems to be supported by experiment.

Results

We analyzed six cases where application of novel or conventional computational methods for protein sequence and structure analysis led to non-trivial predictions that were subsequently supported by direct experiments. We show that, on all six occasions, the original prediction was unjustified, and in at least three cases, an alternative, well-supported computational prediction, incompatible with the original one, could be derived. The most unusual cases involved the identification of an archaeal cysteinyl-tRNA synthetase, a dihydropteroate synthase and a thymidylate synthase, for which experimental verifications of apparently erroneous computational predictions were reported. Using sequence-profile analysis, multiple alignment and secondary-structure prediction, we have identified the unique archaeal 'cysteinyl-tRNA synthetase' as a homolog of extracellular polygalactosaminidases, and the 'dihydropteroate synthase' as a member of the β-lactamase-like superfamily of metal-dependent hydrolases.

Conclusions

In each of the analyzed cases, the original computational predictions could be refuted and, in some instances, alternative strongly supported predictions were obtained. The nature of the experimental evidence that appears to support these predictions remains an open question. Some of these experiments might signify discovery of extremely unusual forms of the respective enzymes, whereas the results of others could be due to artifacts.