David Parkin Visiting Professorship (Vicent Moliner)

Computational modelling of chemical and biochemical systems

The 2013 Nobel Prize in Chemistry was awarded for developments in the computational simulation of complex chemical systems which we ourselves began to apply to enzyme-catalysed reactions while the nominee was a postdoc in Bath during 1996/97. Combining our complementary areas of specific expertise from recent years, we now propose to apply these modern methods for computational simulation to investigate the subtle consequences of selectively changing the mass of one or more atoms on the rate of a chemical reaction catalysed by a protein. These ‘kinetic isotope effects’ are used as experimental probes of the structural changes that occur during chemical reaction and have been applied as part of a procedure for rational drug design. Recently, however, our studies have indicated that the electrostatic environment around a site of isotopic substitution may have a significant influence that has not previously been taken into account in the interpretation of experimental kinetic isotope effects. We will critically assess these influences as they affect two enzymes of topical interest. One catalyses transfer of a methyl group, the other catalyses the break-up of a chain of sugar molecules. Both types of process are of ubiquitous importance in biology and have immense potential impact.