Modeling Isotope Effects on Enzyme-Catalyzed Reactions

8 Modeling Isotope Efleets on Enzyme-Catalyzed Reactions 

In the absence of definitive information about the structure of the active site theoretical modeling of enzyme catalyzed reactions is difficult but not impossible. These difficulties are caused by the extremely large size of the enzyme-substrate-solvent system which typically comprises thousands or tens of thousands of atoms so that direct theoretical treatment at the microscopic quantum mechanical level is not yet practical. The computational demand is simply too enormous. As a compromise, a scheme generally referred to as QM/MM (quantum mechanics/molecular mechanics) has been devised. In QM/MM calculations, the bulk of the enzyme-solvent system (i.e. most of the atoms) is treated at a low cost, usually at the molecular mechanics (MM) level, while the more nearly correct and much more expensive quantum level (QM) computation is applied only to the reaction center (active site). 

The MM approach contrasts with the quantum mechanical (QM) part of the modeling which is restricted to the immediate area of the active site and considers either all electrons (or sometimes just outer shell electrons) explicitly in arriving at a first principle evaluation by solving the Schrodinger equation to deduce the local potential energy surface for the active site. 

1 Quantum Mechanical Dynamical Effects for an Enzyme Catalyzed Proton Transfer Reaction 

The Truhlar group has reported an interesting theoretical study of H/D kinetic isotope effects for conversion of 2 phospho-D-glycerate to phosophoenolpyruvate catalyzed by the yeast enolase enzyme. The proton transfer step (first reaction step in Fig. 11.10) is the rate limiting step and was chosen for theoretical study. The KIE for proton/deuteron transfer is kn/kD = 3.3 at 300 K. 

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Modeling Isotope Effects on Enzyme-Catalyzed Reactions... 

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