Structure-based model of allostery predicts coupling between distant sites

TLDR: A model that varies the size of the allosteric site and its interactions to construct a series of energy landscapes with pronounced minima corresponding to both the effector bound and unbound crystal structures is applied to three proteins with experimentally characterized transitions.

Abstract: Allostery is a phenomenon that couples effector ligand binding at an allosteric site to a structural and/or dynamic change at a distant regulated site. To study an allosteric transition, we vary the size of the allosteric site and its interactions to construct a series of energy landscapes with pronounced minima corresponding to both the effector bound and unbound crystal structures. We use molecular dynamics to sample these landscapes. The degree of perturbation by the effector, modeled by the size of the allosteric site, provides an order parameter for allostery that allows us to determine how microscopic motions give rise to commonly discussed macroscopic mechanisms: (i) induced fit, (ii) population shift, and (iii) entropy driven. These mechanisms involve decreasing structural differences between the effector bound and unbound populations. A metric (ligand-induced cooperativity) can measure how cooperatively a given regulated site responds to effector binding and therefore what kind of allosteric mechanism is involved. We apply the model to three proteins with experimentally characterized transitions: (i) calmodulin-GFP Ca2+ sensor protein, (ii) maltose binding protein, and (iii) CSL transcription factor. Remarkably, the model is able to reproduce allosteric motion and predict coupling in a manner consistent with experiment.