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| Adrian Mulholland, University of Bristol |
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Adrian Mulholland gained his D.Phil. from Oxford University, working with Prof. Graham Richards on the modelling of enzymes with combined quantum mechanics/molecular mechanics methods. This followed a short period working for ICI Pharmaceuticals (now AstraZeneca). He was a Wellcome Trust International Prize Research Travelling Research Fellow, working with Prof. Martin Karplus (Harvard University). He has worked at the University of Bristol, UK, since 1997, as a Wellcome Trust Fellow, EPSRC Advanced Research Fellow, and Lecturer in Chemistry. He is a founder member of the Centre for Computational Chemistry at Bristol. His research interests include enzyme reaction mechanisms and catalysis, ligand binding and protein dynamics. Quantum chemical and combined quantum mechanics/molecular mechanics (QM/MM) methods are a particular focus in the work of his research group.
Recent publications
Ranaghan K.E. & Mulholland AJ ‘Conformational effects in enzyme catalysis: QM/MM free energy calculation of the 'NAC' contribution in chorismate mutase’. Chem. Commun. (2004 ) 1238-1239.
Ranaghan KE, Ridder L, Szefczyk B, et al. ‘Transition state stabilization and substrate strain in enzyme catalysis: ab initio QM/MM modelling of the chorismate mutase reaction’ Org. Biomol. Chem. (2004) 2 968-980
Bathelt CM, Ridder L, Mulholland AJ, et al. ‘Aromatic hydroxylation by cytochrome P450: Model calculations of mechanism and substituent effects’ J Am. Chem. Soc. (2003) 125 15004-15005.
L.Ridder, I.M.C.M.Rietjens, J. Vervoort & A.J. Mulholland ‘Quantum Mechanical/Molecular Mechanical Free Energy Simulations of the Glutathione S-Transferase (M1-1) Reaction with Phenanthrene 9,10-Oxide’ J. Am. Chem. Soc. (2002) 124 9926-9936.
L. Ridder, J.N. Harvey, I.M.C.M. Rietjens, J. Vervoort & A.J. Mulholland ‘Ab initio QM/MM modeling of the hydroxylation step in p-hydroxybenzoate hydroxylase’ J. Phys. Chem. B (2003) 107, 2118-2126.
J.C. Hermann, L. Ridder, A.J. Mulholland, & H.-D. Hoeltje ‘Identification of Glu166 as the general base in the acylation reaction of class A beta-lactamases through QM/MM modeling’ J. Am. Chem. Soc. (2003) 125, 9590-9591.
K.E. Ranaghan, L. Ridder, B. Szefczyk, W.A. Sokalski, J.C. Hermann & A.J. Mulholland ‘Insights into enzyme catalysis from QM/MM modelling: transition state stabilization in chorismate mutase’, Mol. Phys. (2003) 101, 2695-2714
L. Ridder & A.J. Mulholland ‘Modeling biotransformation reactions by combined quantum mechanical/molecular mechanical approaches: From structure to activity’ Curr. Topics Medicinal Chem. (2003) 3, 1241-1256.
A.J. Mulholland and L. Ridder ‘Caught in the act: modelling how a biological catalyst works’ CSAR Focus (2003) 10, 12-13.
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Computational Enzymology: insights into mechanisms and catalysis from QM/MM modelling
Adrian Mulholland, Centre for Computational Chemistry, School of Chemistry, University of Bristol, Bristol BS8 1TS, UK
Knowledge of the chemical reaction mechanisms of drug breakdown by enyzmes should contribute significantly to drug development and design. Examples include metabolism of drugs in the body by enzymes such as cytochrome P450 and glutathione transferase, and the breakdown of beta-lactam antibiotics by beta-lactamases, a central component of bacterial antibiotic resistance. Quantum chemical modelling can provide useful insight for small models. For modelling reactions within enzymes (e.g. to examine determinants of specificity), combined quantum mechanics/molecular mechanics (QM/MM) methods are a good approach. A small region at the active site is treated at the QM level, and interacts with the proteins and solvent environment, which is represented more simply by a molecular mechanics potential function. The QM treatment can be at the semiempirical, ab initio or density functional theory level: more approximate semiempirical methods allow molecular dynamics simulations of enzyme reactions to be performed, while higher level density functional techniques can be used to study metalloenzymes, for example. Close interaction with experiment has in several cases allowed the testing and validation of predictions from mechanistic modelling. The results provide practical and useful insight. They also allow detailed analysis of the fundamental features underlying enzyme catalysis. Recent examples of mechanistic modelling include cytochrome P450, for which a predictive relationship for the hydroxylation of aromatic substrates has been developed, and alternative modes of reaction have been demonstrated. QM/MM calculations have determined the acylation mechanism of class A beta-lactamases, and pinpointed a key determinant of stereospecificity in epoxide ring opening in glutathione transferase.
References
C.M. Bathelt et al., J. Am. Chem. Soc., (2003); 125; 15004-15005
K.E. Ranaghan et al., Org. Biomol. Chem., (2004) 7, 968-980
J.C. Hermann et al., J. Am. Chem. Soc., (2003) 125, 9590-9591.
L. Ridder & A.J. Mulholland, Curr. Topics Medicinal Chem., (2003) 3, 1241-1256.
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