Ligand Binding Site Structure Influences the Evolution of Protein Complex Function and Topology

Area of Science:

• Evolutionary biology
• Structural biology
• Biochemistry

Background:

• Protein complex evolution is debated, with stochastic processes proposed as major drivers.
• Understanding how protein structure influences functional evolution is crucial.

Purpose of the Study:

• To investigate the influence of ligand-binding site structure on protein complex evolution.
• To compare evolutionary rates and patterns between different types of protein complexes.

Main Methods:

• Utilized ligand binding as a proxy for protein function.
• Analyzed structural features of ligand-binding sites in protein complexes.
• Compared evolutionary rates and sequence/structural conservation.

Main Results:

• Homomers with multi-chain binding sites (MBSs) exhibit slower functional evolution compared to monomers and other homomers.
• Protein complexes binding cofactors and metals display more conserved quaternary structures.
• Homologous MBS homomers show greater similarity in ligands and binding pockets than monomers and other homomers.

Conclusions:

• Quaternary structure is under strong evolutionary selection in cofactor-binding MBS homomers, contrasting with neutral processes in single-chain binding sites.
• Findings have pharmacological implications for drug design, identifying single-chain binding sites for selective drugs and MBS homomers for broad-spectrum or multitarget agents.