Modulation of kinetic barriers under chemical constraints: a role for allostery in enzyme catalysis

Abstract

Many enzymes undergo conformational changes and are allosteric, with catalytic activities depending on their conformation. We show how such allostery can be essential for overcoming limitations in catalytic efficiency due to a generic chemical constraint, the strong similarity between the different states that reactants adopt as they are chemically transformed from substrate to product. Focusing for clarity on single-step irreversible unimolecular reactions, we analyze different forms that chemical similarities between reactant states can take, and derive in each case the limitations that they impose on catalytic efficiency. We first consider catalysts with no internal degree of freedom, and then show how catalysts with a particular form of two-state allostery can overcome their limitations. Our results confer a fundamental role to conformational changes as a means to specifically stabilize transition states, and therefore ensure efficient catalysis. They also clarify previous explanations regarding the contribution of substrate “handles”, parts of substrates that are not chemically transformed but whose interactions with enzymes can be critical to catalysis. Additionally, we present links to studies in heterogeneous catalysis, where limitations arising from chemical similarities between reactant states pose well-known challenges.