Wide transition-state ensemble as key component for enzyme catalysis

Abstract

Transition-­state (TS) theory has provided the theoretical framework to explain the enor-mous rate accelerations of chemical reactions by enzymes. Given that proteins display large ensem-bles of conformations, unique TSs would pose a huge entropic bottleneck for enzyme catalysis. Toshed light on this question, we studied the nature of the enzymatic TS for the phosphoryl-­transferstep in adenylate kinase by quantum-­mechanics/molecular-­mechanics calculations. We find a struc-turally wide set of energetically equivalent configurations that lie along the reaction coordinate andhence a broad transition-­state ensemble (TSE). A conformationally delocalized ensemble, includingasymmetric TSs, is rooted in the macroscopic nature of the enzyme. The computational results arebuttressed by enzyme kinetics experiments that confirm the decrease of the entropy of activationpredicted from such wide TSE. TSEs as a key for efficient enzyme catalysis further boosts a unifyingconcept for protein folding and conformational transitions underlying protein function.