Reaction modeling treatment goals

Application of CBS extrapolations to the A5-ketosteroid isomerase-catalyzed conversion of A5-androstene-3,17-dione to the A4 isomer (Fig. 4.10) provides a test case for extensions to enzyme kinetics. This task requires integration of CBS extrapolations into multilayer ONIOM calculations [56, 57] of the steroid and the active site combined with a polarizable continuum model (PCM) treatment of bulk dielectric effects [58-60], The goal is to reliably predict absolute rates of enzyme-catalyzed reactions within an order of magnitude, in order to verify or disprove a proposed mechanism. 

Here we give an overview of the current status and perspectives of theoretical treatments of solvent effects based on continuum solvation models where the solute is treated quantum mechanically. It is worth noting that our aim is not to give a detailed description of the physical and mathematical formalisms that underlie the different quantum mechanical self-consistent reaction field (QM-SCRF) models, since these issues have been covered in other contributions to the book. Rather, our goal is to illustrate the features that have contributed to make QM-SCRF continuum methods successful and to discuss their reliability for the study of chemical reactivity in solution. 

This contribution reviews computational results for three classes of reaction mechanisms proposed for ODCase. Firstly, the mechanism that assumes protonation of C6 concerted with decarboxylation is described. Secondly, the base protonation mechanisms are reviewed. Finally, a shorter treatment is given of a reaction mechanism where the C-C bond is broken before the proton attaches to the base. All values in the review are obtained by the use of QM models of the active site. Effects of different residues on the reaction barrier are analyzed when going from small to large QM models. A QM/MM treatment is applied to each mechanism to see whether this treatment has any major effect on the calculated results. The goal of the review is to provide information regarding the activity of ODCase and to shed light on the requirements on QM models that are applied to enzymatic systems. 

One of the goals of a theory of condensed-phase chemical reactions is the calculation of the rate coefficient. The apparatus of linear response theory can be brought to bear on this problem for reactions taking place close to chemical equilibrium, and formal correlation function expressions for the rate coefficient can be derived. Of course, the dynamics of a liquid-state reacting mixture are not simple and these expressions are difficult to evaluate however, molecular dynamics simulations for simple systems are now possible and provide insight into the details of the reactive event and how it couples to solvent motions, as well as numerical estimates of the rate coefficient. Theoretical treatments necessarily model the full many-particle dynamics by stochastic equations of motion, and it is in the development and utilization of such models that most progress has been made in the theory of condensed-phase reaction rates. 

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