Quantum chemical analysis of reaction paths in chorismate mutase: Conformational effects and electrostatic stabilization

Abstract

AbstractWe have performed a detailed, quantum chemical, decomposition analysis of the physical nature of key interactions in the model enzyme chorismate mutase (CM), for several active conformations produced by high level combined quantum mechanics/molecular mechanics (QM/MM) modeling. In opposition to our previous study, interactions between selected residues in the active site of CM were analysed along the whole reaction path, for several paths. The interaction energy is calculated up to Møller–Plesset second order level of theory and decomposed into physically meaningful components (electrostatic, exchange, delocalization, and electron correlation). This analysis shows, that the dominant interaction is differential stabilization by Arg90: this residue significantly stabilizes the transition state (TS) relative to the substrate in all the paths studied. Interactions in the active site of CM are dominated by the electrostatic component, whereas other components, for example electron correlation, are constant during reaction. Electrostatic effects alone are found to be responsible for lowering the barrier for reaction at the active site. Analysis of four reaction paths derived from QM/MM modeling shows that differences in the height of the barrier are due to differences in the electrostatic interactions of several weakly interacting residues. The influence of conformational effects, such as hydroxyl group rotation in the chorismate/TS, and the distance between Arg90 and the reacting chorismate, have also been analysed. The results show that specific conformations provide better activation barrier lowering. Even small changes in the conformation, like rotation of the hydroxyl group in chorismate (substrate), can significantly alter the activation barrier. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007