title: Transition state theory can be used in studies of enzyme catalysis: lessons from simulations of tunnelling and dynamical effects in lipoxygenase and other systems.
abstract: The idea that enzyme catalysis involves special factors such as coherent fluctuations, quantum mechanical tunnelling and non-equilibrium solvation (NES) effects has gained popularity in recent years. It has also been suggested that transition state theory (TST) cannot be used in studies of enzyme catalysis. The present work uses reliable state of the art simulation approaches to examine the above ideas. We start by demonstrating that we are able to simulate any of the present catalytic proposals using the empirical valence bond (EVB) potential energy surfaces, the dispersed polaron model and the quantized classical path (QCP) approach, as well as the approximate vibronic method. These approaches do not treat the catalytic effects by phenomenological treatments and thus can be considered as first principles approaches (at least their ability to compare enzymatic reaction to the corresponding solution reactions). This work will consider the lipoxygenase reaction, and to lesser extent other enzymes, for specific demonstration. It will be pointed out that our study of the lipoxygenase reaction reproduces the very large observed isotope effect and the observed rate constant while obtaining no catalytic contribution from nuclear quantum mechanical (NQM) effects. Furthermore, it will be clarified that our studies established that the NQM effect decreases rather than increases when the donor-acceptor distance is compressed. The consequences of these findings in terms of the temperature dependence of the kinetic isotope effect and in terms of different catalytic proposals will be discussed. This paper will also consider briefly the dynamical effects and conclude that such effects do not contribute in a significant way to enzyme catalysis. Furthermore, it will be pointed out that, in contrast to recent suggestions, NES effects are not dynamical effects and should therefore be part of the activation free energy rather than the transmission factor. In view of findings of the present work and our earlier works, it seems that TST provides a quantitative tool for studies of enzyme catalysis and that the key open questions are related to the nature of the factors that lead to transition state stabilization.
authors.affiliation: Department of Chemistry, University of Southern California, 3620 South McClintock Avenue, Los Angeles, CA 90089-1062, USA.
authors.forename: Mats H M
authors.initials: MH
authors.lastname: Olsson
authors.forename: Janez
authors.initials: J
authors.lastname: Mavri
authors.forename: Arieh
authors.initials: A
authors.lastname: Warshel
mesh_terms: D002384:Catalysis; D003198:Computer Simulation; D006859:Hydrogen / Q000737:chemistry*; D007700:Kinetics; D008084:Lipoxygenase / Q000737:chemistry*; D008956:Models, Chemical; D011789:Quantum Theory; D013696:Temperature
chemical_list: D006859:Hydrogen; D008084:Lipoxygenase