Simulations of Enzyme Reaction Mechanisms in Active Sites: Accounting for an Environment Which Is Much More Than a Solvent Perturbation (original) (raw)

Abstract

The goal of this chapter is to outline the special challenges faced in using computational methods to define the reaction mechanisms of enzymes. Our approach is to set the problem in the context of the special chemical and structural features which differentiate enzymes from other types of catalysts, and the limitations of experiment in probing these features and defining their contributions to the reaction facilitation. We then briefly discuss the types of computational methods available and how they can be applied to an enzyme problem. Two major features – the roles of active-site protons and water molecules, and enzyme conformational flexibility – are illustrated by results from our simulation work on dihydrofolate reductase. After briefly reviewing published work, we focus on two novel simulation protocols and methods we have recently developed, combining the use of ONIOM ab initio QM/MM calculations and MD simulations with semiempirical QM/MM potentials, to address issues of tr...

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