Recent advances in quantum mechanical/molecular mechanical calculations of enzyme catalysis: hydrogen tunnelling in liver alcohol dehydrogenase and inhibition of elastase by α-ketoheterocycles |
| |
Authors: | Gary Tresadern Paul F Faulder M Paul Gleeson Zubeir Tai Grant MacKenzie Neil A Burton Ian H Hillier |
| |
Institution: | (1) Department of Chemistry, University of Manchester, Manchester, M13 9PL, UK, GB |
| |
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.
Recieved 3 October 2001 / Accepted: 6 September 2002 / Published online: 31 January 2003
Contribution to the Proceedings of the Symposium on Combined QM/MM Methods at the 222nd National Meeting of the American
Chemical Society, 2001
Correspondence to: I. H. Hillier
Acknowledgements. We thank EPSRC and BBSRC for support of the research and D.G. Truhlar for the use of the POLYRATE code. |
| |
Keywords: | : Liver alcohol dehydrogenase – Methylamine dehydrogenase – Quantum mechanical/molecular mechanical methods – Variational transition-state theory – Tunnelling |
本文献已被 SpringerLink 等数据库收录! |
|