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Atomic analysis of promoting vibrations in the vibrationally assisted model of enzymic hydrogen tunneling.

Reference	BB/C003896/1
Principal Investigator / Supervisor	Professor Nigel Scrutton
Co-Investigators / Co-Supervisors	Professor David Leys, Professor Michael Sutcliffe
Institution	The University of Manchester
Department	Life Sciences
Funding type	Research
Value (£)	483,422
Status	Completed
Type	Research Grant
Start date	01/09/2005
End date	30/04/2010
Duration	56 months

Abstract

Enzymes are extremely efficient catalysts that can achieve rate enhancements of up to 10 to the power of 21 over the uncatalysed reaction rate. Our quest to understand the physical basis of this catalytic power, pivotal to our exploitation of enzymes in chemical, biomedical and biotechnological processes is challenging, and has involved sustained and intensive research efforts in the physical and life sciences for over 100 years. Recent years have witnessed new and important activity in this area, and extended our theoretical understanding beyond the shortcomings of semi-classical transition state theory to include roles for protein motion, low barrier hydrogen bonds and quantum mechanical tunnelling. New theoretical frameworks and experimental observations are emerging that help explain the catalytic potency of enzymes. Quantum tunnelling of hydrogen has now been observed experimentally through studies of kinetic isotope effects in a number of enzymes, supported by computational simulations of catalysis. We are now at an exciting stage in enzymology where new theory is required that explicitly recognises a role for quantum tunnelling and protein motion in enzymic reactions. In developing this new conceptual framework that explains more fully the catalytic power of enzymes, our abilities to understand, rationally design and redesign biological catalysts, for exploitation in biotechnological and industrial applications, are strengthened, and the prospects for therapeutic intervention are improved. Enzymic H-tunnelling is now accepted as a major component of catalysis involving H-transfer. Understanding factors that drive this tunnelling reaction is key to understanding a large number of reactions in biology; CH bond cleavage occurs in approximately 50 per cent of all biological reactions, and all of these are likely to tunnel to some degree. A number of key questions now need to be addressed, these include: the nature of the coupling between protein dynamics and quantum tunnelling, the role of potential energy barrier profile (in particular width) on reaction kinetics, the interpretation of isotope effects in probing tunnelling regimes, the development of new theory to accommodate dynamics and tunnelling in catalysis, computational simulations of reactions as a basis for understanding catalysis, and facilitating enzyme redesign using a more appropriate conceptual framework. The wide-ranging implications of quantum tunnelling introduce a paradigm shift in our understanding of enzyme catalysis, inhibition and design, and further progress in this area requires a multidisciplinary approach involving contributions from both the life and physical sciences.

Summary

unavailable

Committee	Closed Committee - Biomolecular Sciences (BMS)
Research Topics	Industrial Biotechnology, Structural Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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