On the relationship between folding and chemical landscapes in enzyme catalysis.

Elucidating the relationship between the folding landscape of enzymes and their catalytic power has been one of the challenges of modern enzymology. The present work explores this issue by using a simplified folding model to generate the free-energy landscape of an enzyme and then to evaluate the activation barriers for the chemical step in different regions of the landscape. This approach is used to investigate the recent finding that an engineered monomeric chorismate mutase exhibits catalytic efficiency similar to the naturally occurring dimer even though it exhibits the properties of an intrinsically disordered molten globule. It is found that the monomer becomes more confined than its native-like counterpart upon ligand binding but still retains a wider catalytic region. Although the overall rate acceleration is still determined by reduction of the reorganization energy, the detailed contribution of different barriers yields a more complex picture for the chemical process than that of a single path. This work provides insight into the relationship between folding landscapes and catalysis. The computational approach used here may also provide a powerful strategy for modeling single-molecule experiments and designing enzymes.