EVOLUTIONARY CONSTRAINT NETWORKS IN LIGAND-BINDING DOMAINS: AN INFORMATION-THEORETIC APPROACH

SYLVIA B. NAGL, JAMES FREEMAN, TEMPLE F. SMITH
1998 Biocomputing '99  
Ligand-binding sites in homologous protein domains can diverge greatly during evolution. This poses a particularly interesting problem in those cases where the ligand-binding site is situated in, or close to, the domain core, or where ligand-docking induces dramatic conformational changes. These features are present in many receptors and enzymes; the hormone-binding domain of the nuclear receptors for steroids and retinoids, for example, exhibits both characteristics. It is therefore of great
more » ... terest to determine how binding sites for diverse ligands evolve in core regions of structurally dynamic domains. Are evolutionary changes locally restricted to the ligand-binding site, or are they distributed throughout the domain? We describe here an information-theoretic approach for the study of covariation between ligand-contacting residues and compensatory mutations that preserve the structural integrity and the conformational dynamics of ligand-binding domains. We apply this method to the analysis of the nuclear receptor ligand-binding domain and show that the ligand-contacting residues in the hormone-binding pocket are evolutionarily linked to an extensive network of covarying positions.
doi:10.1142/9789814447300_0009 fatcat:rmqg4zmbrbdyzjtk5xaig2z5fu