Wild-type and molten globular chorismate mutase achieve comparable catalytic rates using very different enthalpy/entropy compensations

The origin of the catalytic power of enzymes with a meta-stable native state, e.g. molten globular state, is an unsolved challenging issue in biochemistry. To help understand the possible differences between this special class of enzymes and the typical ones, we report here computer simulations of the catalysis of both the well-folded wild-type and the molten globular mutant of chorismate mutase. Using the ab initio quantum mechanical/molecular mechanical minimum free-energy path method, we determined the height of reaction barriers that are in good agreement with experimental measurements. Enzyme-substrate interactions were analyzed in detail to identify factors contributing to catalysis. Computed angular order parameters of backbone N-H bonds and side-chain methyl groups suggested site-specific, non-uniform rigidity changes of the enzymes during catalysis. The change of conformational entropy from the ground state to the transition state revealed distinctly contrasting entropy/enthalpy compensations in the dimeric wild-type enzyme and its molten globular monomeric variant. A unique catalytic strategy was suggested for enzymes that are natively molten globules: some may possess large conformational flexibility to provide strong electrostatic interactions to stabilize the transition state of the substrate and compensate for the entropy loss in the transition state. The equilibrium conformational dynamics in the reactant state were analyzed to quantify their contributions to the structural transitions enzymes needed to reach the transition states. The results suggest that large-scale conformational dynamics make important catalytic contributions to sampling conformational regions in favor of binding the transition state of substrate.