| EPSRC Reference: |
GR/S80486/01 |
| Title: |
Tunnelling Contributions to Kinetic Isotope Effects in Intramolecular Hydron Transfers |
| Principal Investigator: |
Watt, Dr C |
| Other Investigators: |
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| Researcher Co-Investigators: |
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| Project Partners: |
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| Department: |
Chemistry |
| Organisation: |
University of Manchester, The |
| Scheme: |
Standard Research (Pre-FEC) |
| Starts: |
01 October 2004 |
Ends: |
31 March 2008 |
Value (£): |
218,979
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| EPSRC Research Topic Classifications: |
| Catalysis & enzymology |
Chemical Biology |
| Gas & Solution Phase Reactions |
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| EPSRC Industrial Sector Classifications: |
| Pharmaceuticals and Biotechnology |
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Summary on Grant Application Form |
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This proposal responds to recent exciting and controversial reports of large temperature-independent kinetic isotope effects in some enzyme-catalysed proton, hydride and hydrogen atom transfers. The data therein signal large contributions to reactivity from quantum mechanical tunnelling, and it has been suggested that tunnelling might occur widely in enzyme-catalysed reaction where the chemical stage involves transfer of hydrogen (especially in the intrinsically difficult cleavages of C-H bonds), because of evolutionary pressures to maximise enzyme efficiency.We accept these reports and the inference of high tunnelling contributions. For us, the remaining and very interesting chemical question is not whether the tunnelling occurs, but how the enzymes that catalyse these reactions achieve the enhanced contributions at physiological temperatures.Current theories focus on the role of protein dynamics, and a range of computational studies have supported this, post facto. The test of theory, however, is not its ability to rationalise but to predict, so we will carry out computational and experimental studies on intramolecular proton transfers in relatively small and synthetically accessible carbon acids. These will model features of the enzymic reactions. Rates, kinetic isotope effects and temperature dependences will be measured for intramolecular and competing intermolecular deprotonations. Experimental results will be compared with those of computational studies, and used to validate or refine theoretical models to provide a better qualitative and quantitative understanding of the factors promoting tunnelling in biochemical processes.A mark of success in this project would be the computationally assisted design of a relatively small molecule predicted to show enhanced tunnelling, a quantitative estimate of the contribution, and a subsequent synthesis and kinetic characterization of this compound.
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Key Findings |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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Potential use in non-academic contexts |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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Impacts |
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| Description |
This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk |
| Summary |
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| Date Materialised |
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Sectors submitted by the Researcher |
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This information can now be found on Gateway to Research (GtR) http://gtr.rcuk.ac.uk
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| Project URL: |
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| Further Information: |
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| Organisation Website: |
http://www.man.ac.uk |