PhD project:

Modelling the Evolution of Enzyme Catalysis


Dr John Mitchell, Biomolecular Sciences, University of St Andrews

funding details:

Competition Funded Project - UK/EU Students only

closing date:

31 Mar 2010


Contact: 01334 467259

In this project, we will develop a computational model for how enzyme mechanisms evolve. Our group's previous work has developed reaction step fingerprints containing information about how the bond order, charge, and chemical connectivity change in each reaction step in our MACiE database of enzyme-catalysed reactions. The fingerprints provide a fine-tuneable means of quantifying mechanism-based similarities between enzyme-catalysed chemical reactions, which can also be used for clustering. First, the pairwise similarities between the steps in two reactions are computed. A global alignment between the two series of steps is then performed using the Needleman-Wunsch algorithm, just as for sequence alignment in bioinformatics. Existing evolutionary models are designed for comparing DNA or protein sequences, and consider insertions, deletions and mutations as the units of evolutionary change. However, an evolutionary model for reaction mechanisms must be adapted in order to compare chemical reactions.

We will create a simulation using a population of model enzyme-catalysed reactions, mimicking a state early in evolutionary history, and allow them to evolve in EC space. The reactions will consist of steps and be represented, in a manner familiar from genetic algorithms, by "chromosomes" describing the chemical properties of each step. Parameters will control the likelihood of different kinds of evolutionary event, such as a change of substrate with the same underlying chemical mechanism, taking place. The simulations will be calibrated, and then compared with the results from a study of real-world convergent and divergent evolution.