On the relationship between folding and chemical landscapes in enzyme catalysis

Abstract

Elucidating the relationship between the free energy 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 evaluating the activation barriers for the chemical step in different regions of the folding landscape. This approach is used to investigate the recent finding that an engineered monomeric chorismate mutase (CM) exhibits catalytic efficiency similar to the naturally occur dimer even though it exhibits the properties of an intrinsically disordered molten globule. It is found that the molten globule becomes more confined than its native-like counterpart upon ligand binding but still retains a somewhat wider catalytic region. Although the overall rate acceleration is still determined by the reduction of the reorganization energy, the detailed contribution of different barriers provides a more complex picture for the chemical process than that of a single path. This study provides the first systematic study of the relationship between folding landscapes and catalysis. The computational approach employed here may also provide a powerful strategy for modeling single molecule experiments and for enzyme design.