Abstract
The simulation of hydrogen transfer in enzymes provides a uniquely detailed atomistic insight into the reaction. Despite recent advances, such simulations remain challenging due to the importance of both electronic and nuclear quantum effects as well as the effects of protein motion. The incorporation of electronic quantum effects is required for the description of the breakage and formation of chemical bonds. Nuclear quantum effects, such as zero-point energy and hydrogen tunnelling, are also significant. However, over the past decade – with the enhancements in both computer power and theoretical approaches – computational simulations have become increasingly attractive in the study of hydrogen-transfer reactions in enzymes. They can complement experimental studies by providing insight that is difficult to access by experimental approaches, and make predictions that can be tested experimentally. The interplay between experiment and calculations can yield a remarkably complete description of an enzyme-catalysed hydrogen-transfer process – computational simulations have played a major role in furthering our understanding at the atomic level. Computational simulations vary greatly in the level of accuracy they provide. Broadly speaking, they can be divided into two categories molecular mechanical (MM) and quantum mechanical (QM) methods (see Chapter 2). This chapter discusses these methods, how they can be combined to allow larger systems to be studied quantum mechanically, and how the H-tunnelling event can be simulated and rates and kinetic isotope effects (KIEs) calculated. To illustrate these methods, the proton-tunnelling event catalysed by the enzyme aromatic amine dehydrogenase (AADH) with tryptamine as substrate is presented as a case study.