title: Differential transition-state stabilization in enzyme catalysis: quantum chemical analysis of interactions in the chorismate mutase reaction and prediction of the optimal catalytic field.
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 the stabilization 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 structures derived from ab initio QM/MM modeling of Bacillus subtilis chorismate mutase. Significant TS stabilization by approximately -23 kcal/mol [MP2/6-31G(d)] relative to the bound substrate is in agreement with that of previous QM/MM modeling and contrasts with suggestions that catalysis by this enzyme arises purely from 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 by electrostatic effects. Analysis of the differential electrostatic potential of the TS and substrate allows calculation 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 of charged active site residues correspond closely to the optimal catalytic field, showing that the enzyme has evolved specifically to stabilize the TS relative to the substrate.
authors.affiliation: Institute of Physical and Theoretical Chemistry, Wrocław University of Technology, Wyb. Wyspiańskiego 27, 50-370 Wrocław, Poland. borys.szefczyk@pwr.wroc.pl
authors.forename: Borys
authors.initials: B
authors.lastname: Szefczyk
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Mulholland
authors.forename: Kara E
authors.initials: KE
authors.lastname: Ranaghan
authors.forename: W Andrzej
authors.initials: WA
authors.lastname: Sokalski
mesh_terms: D002384:Catalysis; D002826:Chorismate Mutase / Q000737:chemistry* / Q000378:metabolism*; D002827:Chorismic Acid / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000378:metabolism; D053138:Cyclohexenes; D004795:Enzyme Stability; D008956:Models, Chemical; D008958:Models, Molecular; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D003509:Cyclohexanecarboxylic Acids; D053138:Cyclohexenes; D002826:Chorismate Mutase; D002827:Chorismic Acid; C005550:prephenic acid