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Details of Grant 

EPSRC Reference: EP/C532910/1
Title: Accurate QM/MM methods for modelling enzyme catalysis
Principal Investigator: Manby, Professor FR
Other Investigators:
Mulholland, Professor AJ Harvey, Professor J
Researcher Co-Investigators:
Project Partners:
University of Stuttgart
Department: Chemistry
Organisation: University of Bristol
Scheme: Standard Research (Pre-FEC)
Starts: 11 August 2005 Ends: 10 August 2009 Value (£): 260,745
EPSRC Research Topic Classifications:
Catalysis & enzymology High Performance Computing
EPSRC Industrial Sector Classifications:
Pharmaceuticals and Biotechnology
Related Grants:
Panel History:  
Summary on Grant Application Form
A deeper understanding of the catalytic mechanisms of enzymes is crucial for future developments and applications of biochemistry and medicine. Computational models in which classical molecular mechanics (MM) is used to treat the protein and bulk solvent and quantum mechanics (QM) is applied to the reactive centre have proven invaluable tools in this effort. Their applicability and accuracy has, however, been limited by the low levels of QM theory that are currently feasible. In particular the semi-empirical and HF methods commonly used are inapplicable to many important types of system, and often fail to describe even quantitatively important interactions in the enzyme environment. Several factors affect the accuracy of these QM/MM methods, including the size of the QM region, the level of theory used in the QM region, and the accuracy of the treatment of sampling. The aim of the current proposal is to improve dramatically on the accuracy of QM/MM methods, opening up a whole new range of problems - not only of biochemical interest - to quantitative analysis. This will be achieved (1) by using direct dynamics with a density functional theory treatment of the QM region; (2) by using state-of-the-art ab initio QM methods, which have been developed by the P1 and collaborators, including fast local MP2 methods and even coupled cluster theory in the QM/MM implementation, and using them, for example, to correct the energetics of the reaction paths; and (3) by using efficient methods for the dynamic sampling needed to obtain accurate free energy profiles. This better treatment of the QM region will enable, for the first time, accurate descriptions of hydrophobic interactions and hydrogen bonding in the protein environment, and allow calculations on the catalytic behaviour of metalloenzymes including the effects of the protein environment. The resulting methods will be tested on large model systems and comparisons will be made between QM/MM and pure QM calculations and against experiment. The reaction mechanisms of enzymes such as carboxypeptidase A will be investigated and elucidated using existing and newly developed QM/MM methods.
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Organisation Website: http://www.bris.ac.uk