Abstract
Allosteric regulation involves conformational transitions or fluctuations between a few closely related states, caused by the binding of effector molecules. We introduce a quantity called binding leverage that measures the ability of a binding site to couple to the intrinsic motions of a protein. We use Monte Carlo simulations to generate potential binding sites and either normal modes or pairs of crystal structures to describe relevant motions. We analyze single catalytic domains and multimeric allosteric enzymes with complex regulation. For the majority of the analyzed proteins, we find that both catalytic and allosteric sites have high binding leverage. Furthermore, our analysis of the catabolite activator protein, which is allosteric without conformational change, shows that its regulation involves other types of motion than those modulated at sites with high binding leverage. Our results point to the importance of incorporating dynamic information when predicting functional sites. Because it is possible to calculate binding leverage from a single crystal structure it can be used for characterizing proteins of unknown function and predicting latent allosteric sites in any protein, with implications for drug design.
Highlights
Protein function depends on the balance between different conformational states
Allosteric protein regulation is the mechanism by which binding of a molecule to one site in a protein affects the activity at another site
We show that high binding leverage is a characteristic of both allosteric sites and catalytic sites, emphasizing that both enzymatic function and allosteric regulation require a coupling between ligand binding and protein dynamics
Summary
Protein function depends on the balance between different conformational states. This balance can be shifted by many external factors that regulate protein activity, including localized perturbations such as ligand binding or phosphorylation. The early phenomenological MWC (Monod-Wyman-Changeux) [1] and KNF (Koshland-Nemethy-Filmer) [2] models were devised to explain this cooperativity; the first model states that binding stabilizes one of several available states with emphasis on symmetry conservation [3], whereas the latter assumes an induced-fit scenario. Weber showed that both models can be integrated in a general physical framework [4]. In a recent review Cui and Karplus gave a clear discussion of the relation between the classical models [1,2] and the ‘‘new views’’ of allostery [5,6], pointing out that the MWC/Weber formalism already includes the idea of population shift [7]
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