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Bioinformatics Advance Access published online on March 4, 2005
Bioinformatics, doi:10.1093/bioinformatics/bti347
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© The Author (2005). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received January 24, 2005
Accepted February 19, 2005

Article

REVCOM: a robust Bayesian method for evolutionary rate estimation

A. J. Bordner 1* and R. A. Abagyan 1

1 Molsoft LLC, 3366 North Torrey Pines Court, Suite 300, La Jolla, CA. 92037, USA

* To whom correspondence should be addressed.
A. J. Bordner, E-mail: bordner{at}molsoft.com


  Abstract

Motivation: Evolutionary conservation estimated from a multiple sequence alignment is a powerful indicator of the functional significance of a residue, and helps to predict active sites, ligand binding sites, and protein interaction interfaces. Many algorithms that calculate conservation work well provided an accurate and balanced alignment is used. However, such a strong dependence on the alignment makes the results highly variable. We attempted to improve the conservation prediction algorithm by making it more robust and less sensitive to (i) local alignment errors, (ii) overrepresentation of sequences in some branches, and (iii) occasional presence of unrelated sequences.

Results: A novel method is presented for robust constrained Bayesian estimation of evolutionary rates that avoids overfitting independent rates and satisfies the above requirements. The method is evaluated and compared with an entropy-based conservation measure on a set of 1494 protein interfaces. We demonstrate that about 62% of the analyzed protein interfaces are more conserved than the remaining surface at the 5% significance level. A consistent method to incorporate alignment reliability is proposed and demonstrated to reduce arbitrary variation of calculated rates upon inclusion of distantly related or unrelated sequences into the alignment.

Supplementary Information: The protein-protein interface data set, multiple sequence alignments, and corresponding phylogenetic trees are available at http://www.molsoft.com/~bordner/REVCOM/.


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