title: Benchmarking Quantum Mechanics/Molecular Mechanics (QM/MM) Methods on the Thymidylate Synthase-Catalyzed Hydride Transfer.
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.
authors.affiliation: Departament de Química Física i Analítica, Universitat Jaume I , 12071 Castelló, Spain.|Institute of Applied Radiation Chemistry, Lodz University of Technology , 90-924 Lodz, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Świderek
authors.affiliation: Departament de Química Física i Analítica, Universitat Jaume I , 12071 Castelló, Spain.
authors.forename: Kemel
authors.initials: K
authors.lastname: Arafet
authors.affiliation: Department of Chemistry, University of Iowa , Iowa City, Iowa 52242, United States.
authors.forename: Amnon
authors.identifier: http://orcid.org/0000-0001-8793-8939
authors.initials: A
authors.lastname: Kohen
authors.affiliation: Departament de Química Física i Analítica, Universitat Jaume I , 12071 Castelló, Spain.
authors.forename: Vicent
authors.identifier: http://orcid.org/0000-0002-3665-3391
authors.initials: V
authors.lastname: Moliner