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MBE Advance Access published online on February 4, 2009
Molecular Biology and Evolution, doi:10.1093/molbev/msp020
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© The Author 2009. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Research Article

The effect of sequence evolution on protein structural divergence

Simon G. Williams and Simon C. Lovell*

Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT UK

* To whom correspondence should be addressed: email: simon.lovell{at}manchester.ac.uk, Tel: +44 161 2755748, Fax +44 161 2755082

Received for publication September 8, 2008. Revision received January 23, 2009. Accepted for publication January 26, 2009.

The complex constraints imposed by protein structure and function result in varied rates of sequence and structural divergence in proteins. Analysis of sequence differences between homologous proteins can advance our understanding of structural divergence and some of the constraints that govern the evolution of these molecules. Here, we assess the relationship between amino acid sequence and structural divergence. Firstly, we demonstrate that the relationship between protein sequence and structural divergence is governed by a variety of evolutionary constraints, including solvent exposure and secondary structure. Secondly, although compensatory substitutions are widespread, we find many radical size-changing mutations that are not compensated by neighboring complementary changes. Instead, these non-compensated substitutions are mitigated by alteration of protein structure. These results suggest a combined mechanism of accommodating substitutions in proteins, involving both coevolution and structural accommodation. Such a mechanism can explain previously observed correlated substitutions of residues that are distant both in sequence and structure, allowing an integrated view of sequence and structural divergence of proteins.

Key Words: Protein structure • compensating mutations • structural divergence


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