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Theoretical Chemistry Accounts

, Volume 109, Issue 3, pp 108–117 | Cite as

Recent advances in quantum mechanical/molecular mechanical calculations of enzyme catalysis: hydrogen tunnelling in liver alcohol dehydrogenase and inhibition of elastase by α-ketoheterocycles

  • Gary Tresadern
  • Paul F. Faulder
  • M. Paul Gleeson
  • Zubeir Tai
  • Grant MacKenzie
  • Neil A. Burton
  • Ian H. Hillier
Regular article

Abstract.

 Hybrid quantum mechanical (QM)/molecular mechanical (MM) calculations are used to study two aspects of enzyme catalysis, Kinetic isotope effects associated with the hydride ion transfer step in the reduction of benzyl alcohol by liver alcohol dehydrogenase are studied by employing variational transition-state theory and optimised multidimensional tunnelling. With the smaller QM region, described at the Hartree–Fock ab initio level, together with a parameterised zinc atom charge, good agreement with experiment is obtained. A comparison is made with the proton transfer in methylamine dehydrogenase. The origin of the large range in pharmacological activity shown by a series of α-ketoheterocycle inhibitors of the serine protease, elastase, is investigated by both force field and QM/MM calculations. Both models point to two different inhibition mechanisms being operative. Initial QM/MM calculations suggest that these are binding, and reaction to form a tetrahedral intermediate, the latter process occurring for only the more potent set of inhibitors.

Keywords: Liver alcohol dehydrogenase – Methylamine dehydrogenase – Quantum mechanical/molecular mechanical methods – Variational transition-state theory – Tunnelling 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2003

Authors and Affiliations

  • Gary Tresadern
    • 1
  • Paul F. Faulder
    • 1
  • M. Paul Gleeson
    • 1
  • Zubeir Tai
    • 1
  • Grant MacKenzie
    • 1
  • Neil A. Burton
    • 1
  • Ian H. Hillier
    • 1
  1. 1.Department of Chemistry, University of Manchester, Manchester, M13 9PL, UKGB

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