In silico enzymology
We use a range of computational chemistry and bio/cheminformatics approaches to study a range of (bio)chemical systems, with a major focus on enzymes. Molecular dynamics in combination with homology modelling and molecular docking can generate (literally) working models of proteins, which are difficult or impossible to crystallise. Ab initio and DFT methods are used to model enzyme active sites, study enzyme chemistry, and augment X-ray crystallography studies, e.g. when characterising new cofactors.
The role of quantum mechanics in biological processes
While the physical laws underpinning biochemistry and enzymology are generally classical (Newtonian) in nature, we have shown that quantum mechanical tunnelling can play a major role in enzymatic hydrogen transfer reactions. We are now interested in how ubiquitous this phenomenon is, and whether room temperature tunnelling is also a feature of heavy atom rearrangement and transfer during catalysis. We are also interested in whether enzymes actively exploit tunnelling by coupling environmental dynamics to the reaction coordinate, effectively compressing the reaction barrier. A major focus of our work is the development of models that can ‘join the dots’ between the computational and experimental approaches that are jointly used to study these reactions.
Kinetic models of complex reactions
Much of enzymology hinges on the interpretation of measured rate constants of e.g. enzyme-catalysed turnover. These rate constants are usually extracted from steady-state enzyme assays or from pre-steady state approaches such as stopped-flow spectrometry. Unfortunately, these approaches often only allow the measurements of observed (phenomenological) rate constants. We are interested in developing methods that use numerical modelling and global analysis of kinetic data to extract the microscopic rate constants needed to build kinetic models of complex enzymatic reaction mechanisms.
High pressure spectroscopy
In collaboration with the Scrutton, Waltho and Phillips groups, we are developing high pressure methods of experimentally probing structural and mechanistic aspects of protein and enzyme function. Experimentally, these include stopped-flow, NMR and fluorescence lifetime-based approaches, while we combine these with high pressure molecular dynamics simulations and kinetic modelling.