Investigation of Solvent Effects for the Claisen Rearrangement of Chorismate to Prephenate: Mechanistic Interpretation via Near Attack Conformations
ABSTRACT Solvent effects on the rate of the Claisen rearrangement of chorismate to prephenate have been examined in water and methanol. The preequilibrium free-energy differences between diaxial and diequatorial conformers of chorismate, which had previously been implicated as the sole basis for the observed 100-fold rate increase in water over methanol, have been reframed using the near attack conformation (NAC) concept of Bruice and co-workers. Using a combined QM/MM Monte Carlo/free-energy perturbation (MC/FEP) method, 82%, 57%, and 1% of chorismate conformers were found to be NAC structures (NACs) in water, methanol, and the gas phase, respectively. As a consequence, the conversion of non-NACs to NACs provides no free-energy contributions to the overall relative reaction rates in water versus methanol. Free-energy perturbation calculations yielded differences in free energies of activation for the two polar protic solvents and the gas phase. The rate enhancement in water over the gas phase arises from preferential hydration of the transition state (TS) relative to the reactants via increased hydrogen bonding and long-range electrostatic interactions, which accompany bringing the two negatively charged carboxylates into closer proximity. More specifically, there is an increase of 1.3 and 0.6 hydrogen bonds to the carboxylate groups and the ether oxygen, respectively, in going from the reactant to the TS in water. In methanol, the corresponding changes in hydrogen bonding with first shell solvent molecules are small; the rate enhancement arises primarily from the enhanced long-range interactions with solvent molecules. Thus, the reaction occurs faster in water than in methanol due to greater stabilization of the TS in water by specific interactions with first shell solvent molecules.
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- "Thus, former predictions   of solvent effects for the uncatalyzed rearrangement could be in part affected by an inappropriate assignment of the active species. Jorgensen and coworkers realized of the importance of this issue and re-computed their early studies  by using Monte Carlo free energy perturbation methods under the NAC framework; in their new results , they found a NAC population in water of 82%. This finding contrasts with the value of 10 À4 % provided by Hur and Bruice  and with the conclusion reached by Karplus group  for the CHAIR conformation (see above; in principle, one would expect a greater abundance in water for a ''true'' GS conformation than for a NAC). "
ABSTRACT: The mechanism by which enzymes produce enormous rate enhancements in the reactions they catalyze remains unknown. Two viewpoints, selection of ground state conformations and stabilization of the transition state, are present in the literature in apparent opposition. To provide more insight into current discussion about enzyme efficiency, a two-state model of enzyme catalysis was developed. The model was designed to include both the pre-chemical (ground state conformations) and the chemical (transition state) components of the process for the substrate both in water and in the enzyme. Although the model is of general applicability, the chorismate to prephenate reaction catalyzed by chorismate mutase was chosen for illustrative purposes. The resulting kinetic equations show that the catalytic power of enzymes, quantified as the k(cat)/k(uncat) ratio, is the product of two terms: one including the equilibrium constants for the substrate conformational states and the other including the rate constants for the uncatalyzed and catalyzed chemical reactions. The model shows that these components are not mutually exclusive and can be simultaneously present in an enzymic system, being their relative contribution a property of the enzyme. The developed mathematical expressions reveal that the conformational and reaction components of the process perform differently for the translation of molecular efficiency (changes in energy levels) into observed enzymic efficiency (changes in k(cat)), being, in general, more productive the component involving the transition state.FEBS Letters 05/2006; 580(9):2170-7. DOI:10.1016/j.febslet.2006.03.060 · 3.34 Impact Factor
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ABSTRACT: Standard free energies (DeltaGN degree) for formation of near attack conformers, those ground state conformers that can convert directly to the transition state, were calculated for the Claisen rearrangement of chorismate to prephenate in six different environments: water, wild-type enzymes from Bacillus subtilis and Escherichia coli, their Arg90Cit and Glu52Ala mutants, and the 1F7 catalytic antibody. Values of the calculated DeltaGN degrees and the experimentally determined activation energies (DeltaG++) are linearly related with the slope of approximately equal to 1. This demonstrates that the relative rate of the chorismate --> prephenate reaction is overwhelmingly dependent on the efficiency of formation of near attack conformers in the ground state.Proceedings of the National Academy of Sciences 10/2003; 100(21):12015-20. DOI:10.1073/pnas.1534873100 · 9.81 Impact Factor
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ABSTRACT: The new semiempirical methods, PDDG/PM3 and PDDG/MNDO, have been parameterized for halogens. For comparison, the original MNDO and PM3 were also reoptimized for the halogens using the same training set; these modified methods are referred to as MNDO' and PM3'. For 442 halogen-containing molecules, the smallest mean absolute error (MAE) in heats of formation is obtained with PDDG/PM3 (5.6 kcal/mol), followed by PM3' (6.1 kcal/mol), PDDG/MNDO (6.6 kcal/mol), PM3 (8.1 kcal/mol), MNDO' (8.5 kcal/mol), AM1 (11.1 kcal/mol), and MNDO (14.0 kcal/mol). For normal-valent halogen-containing molecules, the PDDG methods also provide improved heats of formation over MNDO/d. Hypervalent compounds were not included in the training set and improvements over the standard NDDO methods with sp basis sets were not obtained. For small haloalkanes, the PDDG methods yield more accurate heats of formation than are obtained from density functional theory (DFT) with the B3LYP and B3PW91 functionals using large basis sets. PDDG/PM3 and PM3' also give improved binding energies over the standard NDDO methods for complexes involving halide anions, and they are competitive with B3LYP/6-311++G(d,p) results including thermal corrections. Among the semiempirical methods studied, PDDG/PM3 also generates the best agreement with high-level ab initio G2 and CCSD(T) intrinsic activation energies for S(N)2 reactions involving methyl halides and halide anions. Finally, the MAEs in ionization potentials, dipole moments, and molecular geometries show that the parameter sets for the PDDG and reoptimized NDDO methods reduce the MAEs in heats of formation without compromising the other important QM observables.Journal of Computational Chemistry 01/2004; 25(1):138-50. DOI:10.1002/jcc.10356 · 3.60 Impact Factor