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PEDS Advance Access published online on May 23, 2005
Protein Engineering Design and Selection, doi:10.1093/protein/gzi029
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org
Received April 19, 2005
Accepted April 21, 2005

Article

Detection and reduction of evolutionary noise in correlated mutation analysis

Orly Noivirt 1, Miriam Eisenstein 2, and Amnon Horovitz 1*

1 Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel
2 Department of Chemical Research Support, Weizmann Institute of Science, Rehovot 76100, Israel

* To whom correspondence should be addressed.
Amnon Horovitz, E-mail: amnon.horovitz{at}weizmann.ac.il


  Abstract

Direct or indirect inter-residue interactions in proteins are often reflected by mutations at one site that compensate for mutations at another site. Various bioinformatic methods have been developed for detecting such correlated mutations in order to obtain information about intra- and inter-protein interactions. Here, we show by carrying out a correlated mutation analysis for non-interacting proteins that the signal due to inter-residue interactions is of similar magnitude to the ‘noise’ that arises from other evolutionary processes related to common ancestry. A new method for detecting correlated mutations is presented that reduces this evolutionary noise by taking into account evolutionary distances in the protein family. It is shown that this method yields better signal-to-noise ratios and, therefore, can much better resolve, for example, correlated mutations that reflect true inter-residue interactions.

Keywords: bioinformatics; co-evolving residues; coordinated mutations; evolution; tree-based shuffling.
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