Katarzyna Świderek1,2, Kemel Arafet1, Amnon Kohen3, Vicent Moliner1. 1. Departament de Química Física i Analítica, Universitat Jaume I , 12071 Castelló, Spain. 2. Institute of Applied Radiation Chemistry, Lodz University of Technology , 90-924 Lodz, Poland. 3. Department of Chemistry, University of Iowa , Iowa City, Iowa 52242, United States.
Abstract
Given the ubiquity of hydride-transfer reactions in enzyme-catalyzed processes, identifying the appropriate computational method for evaluating such biological reactions is crucial to perform theoretical studies of these processes. In this paper, the hydride-transfer step catalyzed by thymidylate synthase (TSase) is studied by examining hybrid quantum mechanics/molecular mechanics (QM/MM) potentials via multiple semiempirical methods and the M06-2X hybrid density functional. Calculations of protium and tritium transfer in these reactions across a range of temperatures allowed calculation of the temperature dependence of kinetic isotope effects (KIE). Dynamics and quantum-tunneling effects are revealed to have little effect on the reaction rate, but are significant in determining the KIEs and their temperature dependence. A good agreement with experiments is found, especially when computed for RM1/MM simulations. The small temperature dependence of quantum tunneling corrections and the quasiclassical contribution term cancel each other, while the recrossing transmission coefficient seems to be temperature-independent over the interval of 5-40 °C.
Given the ubiquity of hydride-transfer reactions in enzyme-catalyzed processes, identifying the appropriate computational method for evaluating such biological reactions is crucial to perform theoretical studies of these processes. In this paper, the n class="Chemical">hydride-transfer step catalyzed by thymidylate synthase (TSase) is studied by examining hybrid quantum mechanics/molecular mechanics (QM/MM) potentials via multiple semiempirical methods and the M06-2X hybrid density functional. Calculations of protium and tritium transfer in these reactions across a range of temperatures allowed calculation of the temperature dependence of kinetic isotope effects (KIE). Dynamics and quantum-tunneling effects are revealed to have little effect on the reaction rate, but are significant in determining the KIEs and their temperature dependence. A good agreement with experiments is found, especially when computed for RM1/MM simulations. The small temperature dependence of quantum tunneling corrections and the quasiclassical contribution term cancel each other, while the recrossing transmission coefficient seems to be temperature-independent over the interval of 5-40 °C.
Authors: Christopher R Pudney; Sam Hay; Colin Levy; Jiayun Pang; Michael J Sutcliffe; David Leys; Nigel S Scrutton Journal: J Am Chem Soc Date: 2009-12-02 Impact factor: 15.419
Authors: Manuel Delgado; Stefan Görlich; James E Longbotham; Nigel S Scrutton; Sam Hay; Vicent Moliner; Iñaki Tuñón Journal: ACS Catal Date: 2017-04-03 Impact factor: 13.084