Details of Group leader - Prof Mike Sutcliffe
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Post: Professor, SCEAS Phone: +44 (0)161 306 2672 Email: michael.sutcliffe[at]manchester.ac.uk Website: Click Me |
Research We use bioinformatics, cheminformatics and computational chemistry methods to study, at the atomic level, protein-mediated processes underpinning biological catalysis, electron transfer, proton transfer and ion transport. |
Current Research
The role of quantum tunnelling in enzyme-catalysed hydrogen transfer
Our pioneering work on enzyme catalysed hydrogen transfer (e.g. our recent article in Science) has led to a better understanding of enzyme mechanism by providing a new conceptual framework for enzyme catalysis. This has resulted in a paradigm shift away from standard "over the barrier" textbook models of enzyme catalysis to a "through the barrier" model, for which quantum tunnelling is invoked. We are using computational chemistry techniques to study factors controlling H-tunnelling in enzymes. We are investigating the importance of the nature of the energy barrier - the overall shape, rather than simply the height as with transition state theory - in controlling reaction rate. In addition to barrier shape, a key role has also been identified for enzyme motion in driving the tunnelling reaction - we are studying how this is coupled to (drives) the tunnelling event.
Enzyme-catalysed electron transfer
We are also studying the role of dynamics in interprotein electron transfer - in particular how dynamics facilitates electron transfer between partner proteins in weakly assembling electron transfer complexes. Additionally, we are studying the role of the protein environment in controlling the chemistry of redox cofactors.
Drug metabolism by, and drug interactions with, cytochromes P450
Cytochromes P450 are highly reactive with a broad spectrum of organic compounds, and thus play a key role in the handling of xenobiotics within the cell. In particular, we are studying drug metabolism by human P450s and the catalytic role of P450s in Mycobacterium tuberculosis. Our in silico studies are producing predictive models of P450 substrate specificity and selectivity. Additionally, they are successfully guiding the re-engineering of enzyme function.
Ion channels
Many fundamental biological processes rely on the movement of K+ across cell membranes through K+ channels. We are studying the dynamics of, and ligand binding to, a range of K+ channels - in particular, factors at the atomic level that drive K+ channel gating and lead to drug block (particularly with hERG).
Service & Awards
- Member of Biochemical Society Theme Panel II: Molecular Structure and Function
- Member of Management Group of Collaborative Computational Project for Biomolecular Simulation (CCPB)
- Member of EPSRC Peer Review College
- Fellow of the Royal Society of Chemistry
- Royal Society University Research Fellowship (1990-1998)
- SERC/NATO Postdoctoral Fellowship (1988-90)
- Junior Research Fellow, Linacre College, Oxford (1989-90)
Funding
BBSRC - Cancer Research UK - EPSRC - MRC - Novartis - The Wellcome Trust
Recent Publications
- Johannissen, L. O., Hay, S., Scrutton, N. S. & Sutcliffe, M. J., Proton tunnelling in aromatic amine dehydrogenase requires a localized promoting vibration: consistency of simulation and theory with experiment, J. Phys. Chem. B., , 2631-2638, 2007.
- Sutcliffe, M. J., Masgrau, L., Roujeinikova, A., Johannissen, L. O., Hothi, P., Basran, J., Ranaghan, K. E., Mulholland, A. J., Leys, D. & Scrutton, N. S., Hydrogen tunnelling in enzyme-catalyzed H transfer reactions: flavoprotein and quinoprotein systems, Phil Trans. Roy. Soc. Series B., , in press., 2006.
- Masgrau, L., Roujeinikova, A., Johannissen, L. O., Basran, J., Ranaghan, K., Hothi, P., Mulholland, A.J., Sutcliffe, M. J., Scrutton, N. S. & Leys, D., Atomic description of an enzyme reaction dominated by proton tunnelling, Science, 312, 237-341, 2006.
- Marechal, JD, Yu, JL, Brown, S, Kapelioukh, I, Rankin, EM, Wolf, CR, Roberts, GCK, Paine, MJI & Sutcliffe, MJ, In silico and in vitro screening for inhibition of cytochrome P450CYP3A4 by comedications commonly used by patients with cancer, Drug. Metab. Dispos., 34, 534-538, 2006.
- Perry, M, Stansfeld, PJ, Leaney, J, Wood, C, de Groot, MJ, Leishman, D, Sutcliffe, MJ & Mitcheson, JS, Drug binding interactions in the inner cavity of hERG channels: Molecular insights from structure-activity relationships of clofilium and ibutilide analogs, Mol. Pharmacol., 69, 509-519, 2006.
- Messiha, HL, Bruce, NC, Sattelle, BM, Sutcliffe, MJ, Munro, AW & Scrutton, NS, Role of active site residues and solvent in proton transfer and the modulation of flavin reduction potential in bacterial morphinone reductase, J. Biol. Chem., 280, 27103-27110, 2005.