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Deposited research article

Using orthologous and paralogous proteins to identify specificity determining residues

Leonid A Mirny¹ and Mikhail S Gelfand²

¹Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, 77 Massachusetts ave, Cambridge, MA 02139

²IntegratedGenomics-Moscow, P.O.Box 348, Moscow, 117333, Russia

author email corresponding author email

Genome Biology 2002, 3:preprint0002.1-0002.20doi:10.1186/gb-2002-3-3-preprint0002

Published:	19 February 2002

This is the first version of this article to be made available publicly, and no other version is available at present.

Subject areas: Bioinformatics, Genome studies, Methods, Evolution

Abstract

Background

Concepts of orthology and paralogy are become increasingly important as whole-genome comparison allows their identification in complete genomes. Functional specificity of proteins is assumed to be conserved among orthologs and is different among paralogs. We used this assumption to identify residues which determine specificity of protein-DNA and protein-ligand recognition. Finding such residues is crucial for understanding mechanisms of molecular recognition and for rational protein and drug design.

Results

Assuming conservation of specificity among orthologs and different specificity of paralogs, we identify residues which correlate with this grouping by specificity. The method is taking advantage of complete genomes to find multiple orthologs and paralogs. The central part of this method is a procedure to compute statistical significance of the predictions. The procedure is based on a simple statistical model of protein evolution. When applied to a large family of bacterial transcription factors, our method identified 12 residues that are presumed to determine the protein-DNA and protein-ligand recognition specificity. Structural analysis of the proteins and available experimental results strongly support our predictions. Our results suggest new experiments aimed at rational re-design of specificity in bacterial transcription factors by a minimal number of mutations.

Conclusions

While sets of orthologous and paralogous proteins can be easily derived from complete genomic sequences, our method can identify putative specificity determinants in such proteins.