Details of Grant 

EPSRC Reference:	GR/R86119/01
Title:	Insights into enzyme catalysed hydrogen tunnelling at the atomic level using computational chemistry
Principal Investigator:	Mulholland, Professor AJ
Other Investigators:	Sutcliffe, Professor M Scrutton, Professor NS
Researcher Co-Investigators:
Project Partners:
Department:	Chemistry
Organisation:	University of Bristol
Scheme:	Standard Research (Pre-FEC)
Starts:	01 October 2002	Ends:	31 January 2006	Value (£):	78,260
EPSRC Research Topic Classifications:	Catalysis & enzymology Chemical Biology
EPSRC Industrial Sector Classifications:	Pharmaceuticals and Biotechnology No relevance to Underpinning Sectors
Related Grants:	GR/R86102/01
Panel History:
Summary on Grant Application Form
Hydrogen transfer reactions are essential to life - the majority of enzymes catalyse the transfer of hydrogen in some form ( proton, hydride or radical transfer). Correct theoretical treatment of these reactions is therefore pivotal to our understanding of biological catalysis at the atomic level. Our pioneering work in this exciting emerging area has established that quantum mechanical tunnelling is involved in many enzyme catalysed H-transfer reactions. Further, we have established that the degree of H-tunnelling, and the efficiency of reaction, is strongly affected by the protein environment. We have developed a number of enzyme systems that catalyse common reactions in biology for which we have aquired data supporting tunnelling and high resolution X-ray structures. Our studies raise a number of important issues including : (i) how enzymes achieve tunnelling, and how the reaction is affected by protein dynamics, (ii) how different substrates affect the potential energy surface and tunnelling characteristics in a given enzyme, (iii) how site-directed mutagenesis compromises the reaction, and (iv) the role of preorganisation of the enzyme-substrate complex in reaction kinetics. We will address these key issues, building on our earlier computational studies, using combined quantum mechanical/molecular mechanical methods to model the reactions within these enzymes. We will determine reaction paths and kinetic isotope effects. In conjuction with our experimental work, this will develop further a new conceptual framework for enzyme catalysed reactions, giving deeper insight into how efficient hydrogen transfer is achieved.
Key Findings
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Organisation Website:	http://www.bris.ac.uk