President’s Research Scholarship: Fidelity in Terpene Synthase Chemistry: Design of a Valencene Synthase

Cardiff University
School of Chemistry

President’s Research Scholarship
The following funded postgraduate position is available in the group of Prof Rudolf Allemann:

The main aim of the proposed work is to rationally change the specificity of the fungal aristolochene synthase so that it produces valencene without significant loss of catalytic efficiency. A combined computational/experimental approach will be used, and all the relevant steps in the catalytic cycle will be investigated. This includes the formation of the active enzyme-substrate complex, the importance and flexibility of Mg2+ and diphosphate binding in catalysis, the effects of substrate conformation and protein dynamics in selectivity and catalysis, the detailed reaction mechanism followed and the specific role(s) of the enzyme in providing stabilization of carbocationic intermediates during the course of the catalytic cycle. The combined approach requires intensive collaboration between the two UK groups, as well as collaboration with overseas international experts for structural analyses. Experimental methods will include protein modification using site-directed mutagenesis and incorporation of non-natural amino acids using a native chemical ligation approach, organic synthesis of mechanism-based inhibitors, kinetic characterization of enzymes and single crystal protein X-ray crystallography.

Computational methods will include hybrid quantum mechanical/molecular mechanical simulations of reactions and transition states, and molecular dynamics simulations of enzyme-intermediate complexes. By combining results from these multiple disciplines, we will build up extensive and uniquely detailed knowledge on the mechanisms guiding catalysis and specificity in aristolochene synthase and develop protocols to influence these through site-directed mutagenesis. In addition to the main aim, the developed protocols can make other changes to the product distribution possible and can also be applied to other terpene synthase enzymes. This will help unlock the great potential of terpenoids as useful compounds with applications in healthcare, agriculture and bio-energy.

If you are interested and highly motivated to engage in research work in a multidisciplinary group performing research at the interface between the physical and life sciences, we would like to hear from you. The Scholarship will be of interest to the highest quality candidates – those eligible for funding as President Scholars will have a first-class honours degree, or a 2.1 plus a postgraduate Masters degree (or their equivalents). These positions are available from October 2013 and open to EU and EEA students.

For further information about this and other positions see: http://www.cardiff.ac.uk/chemy/staffinfo/allemann/. To apply send your full CV and the contact details of at least 2 professional referees to Prof RK Allemann ([Email Address Removed]). Informal enquiries are welcome.