On the emergence of single versus multi-state allostery

TL;DR

This paper investigates the physical and evolutionary factors that lead to the emergence of single versus multi-state allostery in proteins, revealing that multi-state mechanisms generally provide stronger allosteric effects and evolutionary advantages.

Contribution

It introduces a simplified model showing how different allosteric mechanisms can evolve and identifies conditions favoring multi-state allostery over single-state mechanisms.

Findings

Multi-state allostery confers stronger effects.

Evolution favors multi-state mechanisms when possible.

Physical constraints influence allosteric mechanism emergence.

Abstract

Several physical mechanisms have been proposed to explain allostery in proteins. They differ by the number of internal states that they assume a protein to occupy, leaving open the question of what controls the emergence of these distinct physical forms of allostery. Here, we analyze a simplified model of protein allostery under a range of physical and evolutionary constraints. We find that two archetypal mechanisms can emerge through evolution: a single-state mechanism where ligand binding induces a displacement along a soft normal mode or a multi-state mechanism where ligand binding induces a switch across an energy barrier to a different stable state. Importantly, whenever the two mechanisms are possible, the multi-state mechanism confers a stronger allosteric effect and thus a selective advantage. This work defines the essential constraints on single or multi-state allostery, and sets the stage for a physical theory of its evolutionary origins.