2008 winners

Ben Bulheller is currently writing up his PhD in the group of Prof Jonathan Hirst in the School of Chemistry at the University of Nottingham. Ben plans to undertake research in the group of Prof Shaul Mukamel at the University of Irvine in California. Below he describes the research he will carry out:

Optical spectroscopy is a valuable tool for characterizing protein structure. Recent developments are opening up interesting new areas for the study of ultrafast dynamics. Two-dimensional (2D) coherent third-order approaches promise significant new information beyond that available from established linear counterparts. Ultraviolet (UV) circular dichroism (CD) spectroscopy can provide useful information on the folding dynamics of proteins. By probing electronic transitions, we anticipate that 2DUV will furnish new insights into protein backbone dynamics. In the proposed collaboration, we will bring together molecular dynamics simulations of proteins, quantum chemical ab initio calculations on peptides and state-of-the-art methods for simulating 2D optical spectra.

Jonathan Fuller is currently studying for a PhD in the group of Dr Richard Jackson in the School of Biology at the University of Leeds. Jonathan plans to undertake research in the group of Prof Michael Shirts at the University of Virgina. Below he describes the research he will carry out:

The protein p53 is the major tumour suppressor in humans, regulated by binding to MDM2. Competitive inhibition of MDM2/p53 is being pursued as a target for oncology drugs, since inhibiting this interaction will allow p53 to exert its tumour suppressing capabilities[1]. We are interested in Oligoamides, a class of small molecules that present different functional groups at positions analogous to those of the native peptide sidechains, thus mimicking the natural p53 binding epitope. Our research aims to aid synthetic chemistry efforts and structural studies currently being undertaken at the University of Leeds. In order to guide synthesis of these compounds accurate information on the solubility and likely affinity of these compounds to the MDM2 target is required.

To this end we aim to carry out alchemical free energy calculations to determine the affinity of oligoamides and support docking and experimental studies to develop potent new inhibitors to MDM2. Michael Shirts's research group (currently based at the University of Virginia) has published a number of well-cited recent studies on high precision calculations of solvation in biomolecular systems[2] and on the binding affinity of ligands. He has additionally written several recent reviews on the subject of free energy calculations[3].

Jonathan Fuller and Dr Richard Jackson have recently published a review which gives background information on the topic of protein-protein interaction inhibition[4].

1. Vazquez, A. et al. The genetics of the p53 pathway, apoptosis and cancer therapy. Nature Reviews Drug Discovery 7, 979-987(2008).
2. Shirts, M. R. & Pande, V. S. Solvation free energies of amino acid side chain analogs for common molecular mechanics water models. The Journal of Chemical Physics 122, 134508(2005).
3. Shirts, M., Mobley, D. & Chodera, J. Chapter 4 alchemical free energy calculations: ready for prime time?. Annual Reports in Computational Chemistry 3, 41-59(2007).
4. Fuller, J. C., Burgoyne, N. J. & Jackson, R. M. Predicting druggable binding sites at the protein–protein interface. Drug Discovery Today 14, 155-161(2009).