Emergence of Single- versus Multi-State Allostery

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 a continuum of mechanisms between two archetypes emerges through evolution. In one limit, a single-state mechanism exists where ligand binding induces a displacement along a single normal mode, and in the other limit, a multi-state mechanism exists 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 that distinguish single- and multi-state allostery and sets the stage for a physical theory of its evolutionary origins.Received 18 September 2022Revised 22 May 2023Accepted 21 September 2023DOI:https://doi.org/10.1103/PRXLife.1.023004Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.Published by the American Physical SocietyPhysics Subject Headings (PhySH)Research AreasBiomolecular structureMolecular evolutionProtein dynamics, structure & functionPhysical SystemsProteinsPhysics of Living Systems