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Protein Science (2004), 13:443-456. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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Automated selection of positions determining functional specificity of proteins by comparative analysis of orthologous groups in protein families

Olga V. Kalinina1, Andrey A. Mironov1, Mikhail S. Gelfand1 and Aleksandra B. Rakhmaninova2

1 State Scientific Center GosNIIGenetika, Moscow 113545, Russia
2 Integrated Genomics–Moscow, Moscow 117333, Russia

(RECEIVED May 7, 2003; FINAL REVISION August 4, 2003; ACCEPTED September 3, 2003)



Abstract

The increasing volume of genomic data opens new possibilities for analysis of protein function. We introduce a method for automated selection of residues that determine the functional specificity of proteins with a common general function (the specificity-determining positions [SDP] prediction method). Such residues are assumed to be conserved within groups of orthologs (that may be assumed to have the same specificity) and to vary between paralogs. Thus, considering a multiple sequence alignment of a protein family divided into orthologous groups, one can select positions where the distribution of amino acids correlates with this division. Unlike previously published techniques, the introduced method directly takes into account nonuniformity of amino acid substitution frequencies. In addition, it does not require setting arbitrary thresholds. Instead, a formal procedure for threshold selection using the Bernoulli estimator is implemented. We tested the SDP prediction method on the LacI family of bacterial transcription factors and a sample of bacterial water and glycerol transporters belonging to the major intrinsic protein (MIP) family. In both cases, the comparison with available experimental and structural data strongly supported our predictions.

Keywords: Orthologs; specificity; prediction; mutual information; substitution matrix; cutoff

Reprint requests to: Mikhail S. Gelfand, State Scientific Center GosNIIGenetika, 1st Dorozhny pr., 1, Moscow 113545, Russia; e-mail: gelfand{at}ig-msk.ru; fax: 7-095-315-0501.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03191704.


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