Modelling of Transition States in Condensed Phase Reactivity Studies

Abstract

In this Chapter we describe the calculation of transition states for condensed phase reactions involving catalysis by an enzyme and by a titanosilicate. Transition structures for hydride transfer between NADPH and FAD in the enzyme glutathione reductase have been determined using a QM/MM potential, for two forms of the enzyme, e. coli and human. Both the transition state structures and energies, and the associated kinetic isotope effects are found to differ for the two enzymes. A cluster has been used to model the transition state for alkene epoxidation by hydrogen peroxide, catalysed by titanosilicates, predicting attack of the oxygen atom of the titanium(IV)-hydroperoxide intermediate that is closer to the metal centre.The majority of chemical processes and all biochemical ones occur in the condensed, rather than the gas phase. Methods for modelling the potential energy surfaces associated with gas phase reactions are well established and widely available in quantum chemistry packages. Here, for small and medium size systems results of a "chemical" accuracy may be obtained using widely available distributed computational resources. There is now increasing effort to achieve this degree of realism for condensed phase systems, particularly to understand reactivity and catalysis and hence to aid molecular design across a range of important chemical areas. It is to solve these problems that the traditional methods of both computational chemistry and solid state physics are now being focused. In the latter area, periodic calculations based upon a plane wave pseudopotential (PWP) approach, incorporating the work of Car and Parrinello to permit dynamical simulations to be performed, have been used to study solid state structure and

QUANTUMMECHANICALMETHODS FORENZYMEKINETICS

“…Finally, consideration of multidimensional tunneling contributions is required in calculating the transmission coefficient, particularly for reactions involving hydrogen (H, H + , and H − ) transfer. Although quantum mechanical approaches have been used in various ways for studying condensed-phase systems (24,50), it was only recently that computational studies have fully included all three of these aspects of quantum mechanical effects in calculations including an explicit enzyme environment (48,(51)(52)(53)(54)(55)(56)(57)(58)(59). In what follows, we summarize methods that have been developed by our groups and others for including quantum mechanical contributions in enzyme kinetics modeling.…”

“…Both wild-type enzyme and a mutant were studied. GLUTATHIONE REDUCTASE Transition states were optimized for hydride transfer from nicotinamide adenine dinucleotide phosphate hydride (NADPH) to a flavin cofactor as catalyzed by glutathione reductase (51). The quantum mechanical system was treated by AM1, and the molecular mechanical part of the calculation employed CHARMM and TIP3P; the subsystems were joined by link atoms.…”

“…KIEs were calculated by conventional TST with quantized harmonic vibrations and a Wigner transmission coefficient. The latter is as large as 4.2, and the authors noted that Wigner approximation is not reliable for such a large transmission coefficient (51). enolase.…”