An Assessment of Quaternary Structure Functionality in Homomer Protein Complexes

Area of Science:

• Protein structure and evolution
• Biochemistry and biophysics
• Computational biology

Background:

• Homomeric protein-protein interfaces are proposed to evolve neutrally due to mutation biases.
• The proportion of such non-functional (gratuitous) complexes remains unquantified.
• Understanding the functional significance of homodimerization is crucial for protein evolution studies.

Purpose of the Study:

• To quantify the fraction of homodimers where multimerization is unlikely to contribute to biochemical function.
• To investigate the relationship between interface structure, conservation, and function in homomers.
• To explore the evolutionary pressures shaping homomeric interfaces.

Main Methods:

• Analysis of ligand binding-site structure to predict homomer functionality.
• Quantification of interface conservation and hydrophobicity in homodimers.
• Comparison of evolutionary patterns between multichain binding site (MBS) and single-chain binding site (SBS) homomers.

Main Results:

• Ligand binding-site structure effectively predicts homomer function; MBS homodimers are largely functional.
• A significant fraction (35-42%) of small to medium SBS homodimers with single-chain binding sites may not be functional.
• Interface conservation and co-evolution with binding sites differ significantly between MBS and SBS homomers.
• SBS homomer interfaces show conservation levels similar to solvent-accessible surfaces, unlike MBS homomers.

Conclusions:

• Quaternary structure in a substantial portion of SBS homodimers is unlikely to be functional.
• MBS homomers exhibit stronger interface conservation and co-evolution, supporting their functional roles and allosteric potential.
• The 'hydrophobic ratchet' influences amino acid composition, but interfaces are not in strict mutational equilibrium, with notable cysteine abundance in mutations.