Wr. Atchley et al., Correlations among amino acid sites in bHLH protein domains: An information theoretic analysis, MOL BIOL EV, 17(1), 2000, pp. 164-178
An information theoretic approach is used to examine the magnitude and orig
in of associations among amino acid sites in the basic helix-loop-helix (bH
LH) family of transcription factors. Entropy and mutual information values
are used to summarize the variability and covariability of amino acids comp
rising the bHLH domain for 242 sequences. When these quantitative measures
are integrated with crystal structure data and summarized using helical whe
els, they provide important insights into the evolution of three-dimensiona
l structure in these proteins. We show that amino acid sites in the bHLH do
main known to pack against each other have very low entropy values, indicat
ing little residue diversity at these contact sites. Noncontact sites, on t
he other hand, exhibit significantly larger entropy values, as well as stat
istically significant levels of mutual information or association among sit
es. High levels of mutual information indicate significant amounts of inter
correlation among amino acid residues at these various sites. Using compute
r simulations based on a parametric bootstrap procedure, we are able to par
tition the observed covariation among various amino acid sites into that ar
ising from phylogenetic (common ancestry) and stochastic causes and those r
esulting from structural and functional constraints. These results show tha
t a significant amount of the observed covariation among amino acid sites i
s due to structural/functional constraints, over and above the covariation
arising from phylogenetic constraints. These quantitative analyses provide
a highly integrated evolutionary picture of the multidimensional dynamics o
f sequence diversity and protein structure.