Probing the Dark Energy in the Functional Protein Universe

TL;DR

This paper introduces a method to identify and quantify functional constraints in proteins by comparing physical folding energies with evolutionary landscapes, revealing localized 'Dark Energy' at functional sites.

Contribution

It presents a novel approach to localize and measure Dark Energy in proteins, linking physical energetics with evolutionary constraints to better understand protein function.

Findings

Dark Energy is concentrated at functional sites in proteins.

Approximately 25% of residues in globular proteins show significant Dark Energy.

Functional selection temperature can be derived from the relationship between physical and evolutionary energies.

Abstract

We show how to localize and quantify the functional evolutionary constraints on natural proteins. The method compares the perturbations caused by local sequence variants to the energetics of the protein folding process and to the corresponding change to the apparent selection landscape of sequences over the evolutionary time scale. The difference between the physical folding free energies and the evolutionary free energies can be called a "Dark Energy". We analyse various protein sets and thereby show that Dark Energy is largely localized at functional sites, which are often energetically frustrated from the point of view of folding. Overall, we find that about 25% of the positions of the folded globular proteins display some significant Dark Energy. When a function relies on a free energy that can be thermodynamically quantified, such as a binding energy to a partner, the relationship of this physical free energy with Dark Energy can be used to define a Functional Selection Temperature. We show that selection for folding and binding functions bear similar weights in specific protein-protein interactions.