Protein Engineering, Vol. 12, No. 2, 95-100,
February 1999
© 1999 Oxford University Press
Combining sensitive database searches with multiple intermediates to detect distant homologues
1 Helix Research Institute, 1532–3 Yana, Kisarazu-shi, Chiba, 292, Japan, 3 Biomolecular Structure and Modelling Unit, Department of Biochemistry, University College London, Gower Street, London, UK and 4 Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba 305, Japan
Using data from the CATH structure classification, we have assessed the blastp, fasta, smith–waterman and gapped-blast algorithms, developed a portable normalization scheme and identified safe thresholds for database searching. Of the four methods assessed, fasta, smith–waterman and gapped-blast perform similarly, whereas the sensitivity of blastp was much lower. Introduction of an intermediate sequence search substantially improved the results. When tested on a set of relationships that could not be identified by blastp, intermediate sequences were able to find double the number of relationships identified by the smith–waterman algorithm alone. However, we found that the benefit of using intermediates varied considerably between each family and depended not only on the number of available sequences, but also their diversity. In an attempt to increase sensitivity further, a multiple intermediate sequence search (MISS) procedure was developed. When assessed on 1906 cases from a wide range of homologous families that could not be detected by the previous approaches, MISS was able to identify 241 additional relationships. MISS uses the full extent of sequence diversity to detect additional relationships, but does not consider any structure-specific information. For this reason, it is more generally applicable than fold recognition and threading methods, which require a library of known structures.
Keywords: CATH/intermediate searches/sequence analysis/protein structure
2 Present address: Sanger Centre, Wellcome Trust Genome Campus, Cambridge, UK
4 To whom correspondence should be addressed. Present address: Inpharmatica Ltd, 60 Charlotte Street, London W1P 2AX, UK
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