Model Setup and Procedures for Prediction of Enzyme Reaction Kinetics with QM-Only and QM:MM Approaches

The enzyme-catalyzed reactions are traditionally studied with experimental kinetic assays. The modern theoretical modeling techniques provide a complementary way to investigate these catalytic reactions. Experimental assay frequently does not allow an unequivocal answer to the factors controlling the reaction mechanism. On the other hand, the theoretical experiments provide a precise understanding of the molecular-level steps involved in catalytic reactions. However, modeling requires at least structural data on the enzyme and reactant, and the complexity of the enzyme systems can still be a challenge.In this chapter, we are going to describe how to apply theoretical modeling methods, such as MD simulation, QM-only cluster models of enzyme active site, or QM:MM multiscale modeling to study enzyme kinetics and even to predict kinetic isotope effect (KIE). We present a full protocol that starts from the PDB structure of the enzyme, through MD simulation of enzyme: substrate complex and statistical analysis of MD trajectory, selection of a model of the active site, and study of reaction pathways. We show how theoretical predictions basing on QM-only cluster models, QM:MM model, or multiple QM:MM models derived from QM:MM:MD simulations can be correlated with experimental kinetic results. Finally, we show how one can calculate intrinsic KIE associated with an individual molecular step.