How special is the biochemical function of native proteins?

Area of Science:

• Biochemistry
• Structural Biology
• Protein Engineering

Background:

• Native proteins exhibit diverse biochemical functions crucial for life, including catalysis and interactions.
• A central question is whether these functional properties are rare or inherent to protein structures.

Purpose of the Study:

• To investigate if artificially generated protein structures (ART) possess native-like biochemical functions.
• To compare the functional properties of ART proteins with those of native proteins.

Main Methods:

• Generation of a library of artificial (ART) protein structures selected for thermodynamic stability.
• Computational prediction of small molecule ligand-binding pockets, protein-protein interfaces, and protein-DNA interactions in ART proteins.
• Analysis of metabolic pathway enrichment and active site characteristics in ART proteins.

Main Results:

• ART proteins recapitulate a significant number of native-like properties, including ligand-binding pockets and protein-protein interfaces.
• ART structures are predicted to bind metabolites and are associated with metabolic pathways, notably ancient ones like glycolysis.
• Native-like active sites and a fraction of strong protein-protein and protein-DNA interactions were identified in ART proteins.

Conclusions:

• Biochemical function appears to be an intrinsic feature of protein structures, significantly optimized by evolution.
• The findings suggest that protein function is not exclusively a product of natural selection for specific roles but an inherent property.
• Further research is needed to explore the roles of specificity and promiscuity in cellular biochemical control.