Protein evolution with dependence among codons due to tertiary structure

Mol Biol Evol. 2003 Oct;20(10):1692-704. doi: 10.1093/molbev/msg184. Epub 2003 Jul 28.


Markovian models of protein evolution that relax the assumption of independent change among codons are considered. With this comparatively realistic framework, an evolutionary rate at a site can depend both on the state of the site and on the states of surrounding sites. By allowing a relatively general dependence structure among sites, models of evolution can reflect attributes of tertiary structure. To quantify the impact of protein structure on protein evolution, we analyze protein-coding DNA sequence pairs with an evolutionary model that incorporates effects of solvent accessibility and pairwise interactions among amino acid residues. By explicitly considering the relationship between nonsynonymous substitution rates and protein structure, this approach can lead to refined detection and characterization of positive selection. Analyses of simulated sequence pairs indicate that parameters in this evolutionary model can be well estimated. Analyses of lysozyme c and annexin V sequence pairs yield the biologically reasonable result that amino acid replacement rates are higher when the replacements lead to energetically favorable proteins than when they destabilize the proteins. Although the focus here is evolutionary dependence among codons that is associated with protein structure, the statistical approach is quite general and could be applied to diverse cases of evolutionary dependence where surrogates for sequence fitness can be measured or modeled.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Annexin A5 / chemistry
  • Annexin A5 / genetics
  • Codon*
  • Computational Biology
  • Computer Simulation
  • Data Interpretation, Statistical
  • Evolution, Molecular*
  • Markov Chains
  • Muramidase / chemistry
  • Muramidase / genetics
  • Protein Structure, Tertiary
  • Proteins / chemistry
  • Proteins / genetics*


  • Annexin A5
  • Codon
  • Proteins
  • Muramidase