| Abstract
| - Chorismate mutase is a key model system in the development of theories of enzyme catalysis.To analyze the physical nature of catalytic interactions within the enzyme active site and to estimate thestabilization of the transition state (TS) relative to the substrate (differential transition state stabilization,DTSS), we have carried out nonempirical variation−perturbation analysis of the electrostatic, exchange,delocalization, and correlation interactions of the enzyme-bound substrate and transition-state structuresderived from ab initio QM/MM modeling of Bacillus subtilis chorismate mutase. Significant TS stabilizationby approximately −23 kcal/mol [MP2/6-31G(d)] relative to the bound substrate is in agreement with that ofprevious QM/MM modeling and contrasts with suggestions that catalysis by this enzyme arises purelyfrom conformational selection effects. The most important contributions to DTSS come from the residues,Arg90, Arg7, Glu78, a crystallographic water molecule, Arg116, and Arg63, and are dominated byelectrostatic effects. Analysis of the differential electrostatic potential of the TS and substrate allowscalculation of the catalytic field, predicting the optimal location of charged groups to achieve maximal DTSS.Comparison with the active site of the enzyme from those of several species shows that the positions ofcharged active site residues correspond closely to the optimal catalytic field, showing that the enzyme hasevolved specifically to stabilize the TS relative to the substrate.
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