Investigations of enzyme-catalysed reactions with combined quantum mechanics/molecular mechanics (QM/MM) methods

Abstract

Combined quantum mechanics/molecular mechanics (QM/MM or QM-MM) methods are an excellent approach for modelling the mechanisms of enzyme-catalysed reactions. QM/MM methods allow detailed modelling of reactions in enzymes by coupling quantum chemical calculations on the active site with a simpler, empirical ‘molecular mechanics’ treatment of the rest of the protein. Possible reaction mechanisms can be compared and catalytic interactions analysed. QM/MM calculations can now be carried out for enzyme-catalysed reactions with quantum chemical methods of potentially very high accuracy. More approximate QM methods can allow extensive molecular simulations (e.g. molecular dynamics or Monte Carlo simulations). In this review, QM/MM techniques are outlined and some recent applications to enzyme-catalysed reactions are discussed.

Keywords:

• chorismate mutase
• quantum tunnelling
• cytochrome P450 compound I
• lysozyme
• β-lactamases
• HIV
• computational enzymology

Acknowledgements

A.J. Mulholland is an EPSRC Leadership Fellow, and (with KER) thanks the EPSRC for support. A.J. Mulholland thanks his co-workers in the work described here. Some of the works reviewed here were carried out using the computational facilities of the Advanced Computing Research Centre, University of Bristol (http://www.acrc.bris.ac.uk/acrc/index.htm). We would also like to thank Dr Richard Lonsdale, Dr Alessio Lodola, Dr Marc van der Kamp, Dr Johannes Hermann and Ian Grant for help with the preparation of the figures.