Evolutionary constraint networks in ligand-binding domains: an information-theoretic approach

Area of Science:

• Structural biology
• Evolutionary biology
• Computational biology

Background:

• Ligand-binding sites in homologous protein domains can evolve significantly, particularly when located in core regions or inducing conformational changes.
• This evolutionary divergence is notable in receptors and enzymes like the hormone-binding domain of nuclear receptors.

Purpose of the Study:

• To investigate how ligand-binding sites evolve within structurally dynamic protein domains.
• To determine if evolutionary changes are localized to the binding site or distributed throughout the domain.

Main Methods:

• Development of an information-theoretic approach to study covariation between ligand-contacting residues and compensatory mutations.
• Application of this method to analyze the nuclear receptor ligand-binding domain.

Main Results:

• Identified an extensive network of covarying positions linked to ligand-contacting residues in the nuclear receptor hormone-binding pocket.
• Demonstrated that evolutionary changes are not restricted to the binding site but are distributed across a wider network.

Conclusions:

• Evolutionary adaptations in ligand-binding domains involve coordinated changes across multiple residues, not just those directly interacting with the ligand.
• The findings provide insights into the mechanisms of protein evolution and functional adaptation in dynamic domains.