We focus on understanding the complexity of biological systems at a molecular level. Working at the interface of Biology, Chemistry and Biophysics, we bring new approaches to fundamental biological questions as well as the design of drugs and biomaterials. The work encompasses Physical Biochemistry together with Chemical, Structural and Synthetic Biology.
Integrative and cross-disciplinary approaches are used to tackle contemporary questions in basic biomolecular science and quantify biological processes in the context of both normal healthy function and pathological states. Emphasis is placed on understanding interactions between proteins and bioactive molecules to elucidate reaction mechanisms and pathways. The work combines biochemical and biophysical methods with chemical synthesis, protein design and computational modelling.
There are recognised strengths in biophysical and molecular mechanistic research with a focus on protein dynamics, structural biology and enzymology; we excel in DNA-protein interactions, membrane proteins, protein translocation, assembly and design, and have emerging research programmes in Synthetic Biology.
Research within this theme involves researchers in several Departments, notably Biochemistry and Chemistry. Topics include: DNA-protein interactions, single-molecule studies, drug design, receptor structure and function, neurotrophin-receptor complexes, enzyme mechanism and inhibition, polyketide biosynthesis, membrane-protein folding, protein translocation, photosynthetic reaction centre mechanism, chaperone action, biomolecular modeling and theoretical studies, protein engineering and design, and protein-structure prediction. Techniques range from peptide synthesis, protein production and molecular biology to protein analytical techniques, X-ray crystallography, kinetic measurements, and advanced spectroscopy and microscopy. There are extensive interactions between the Departments of Biochemistry, Chemistry and Physics, for example in the application of NMR and atomic force microscopy.
Protein mediated communications on DNA Investigated in the Department of Biochemistry, by the research groups of Dr Mark Dillingham, Dr Kevin Gaston, Professor Steve Halford, Dr Nigel Savery and Dr Mark Szczelkun. Professor Halford was awarded an FRS for his pioneering work on the mechanisms of DNA-protein reactions.
We are embarking on new avenues of research in DNA, proteins and molecular motors at the single molecule level using total internal reflection microscopy (TIRF) and magnetic tweezers.
Membrane proteins and mechanisms of protein insertion and folding are investigated in the Department of Biochemistry, by Prof Paula Booth, while protein integration and translocation across membranes is investigated by Dr Ian Collinson. Their innovative work has been recognised in the award of the Colworth Medal of the Biochemical Society to Dr Collinson and a Philip Leverhulme Prize and a Royal Society Wolfson Merit Award to Prof Booth.
Methods that could aid the design of new drugs, for example against malaria are developed at the Department of Biochemistry, by Professor Leo Brady’s group. The crystal structure of the cofactor NAD (blue) and an inhibitor (green) bound to lactate dehydrogenase from Plasmodium falciparum, the parasite responsible for the most lethal form of malaria. New structural work is starting on complex protein assemblies with the arrival of Dr Paul Race as a Royal Society University Research Fellow working on polyketide synthase. This will advance existing research into polyketides in the Department of Chemistry led by Professor Tom Simpson FRS.
Better understanding of how enzymes work also promises technological developments with regard to new, environmentally friendly catalysts. Computer modelling can give detailed insight into the fundamental mechanisms of enzyme catalysis. Adrian Mulholland's group in Chemistry works on modelling of enzyme mechanisms, including beta-lactamases (involved in antibiotic resistance) and HIV reverse transcriptase. Calculations have also shown that quantum tunnelling is an important factor in some enzyme-catalysed reactions, for example aromatic amine dehydrogenase.
Protein design is advancing our understanding of how proteins fold by making new protein structures and functions from first principles. For example, Prof Dek Woolfson’s lab, which bridges Chemistry and Biochemistry, is interested in designing peptide-based molecular switches and self-assembling fibres and networks.
Building on Bristol’s strengths in protein design, folding and assembly are new research programmes in Synthetic Biology. In this endeavour, Bristol biochemists, such as Woolfson and Booth, along with Bristol engineers are planning to construct complex self-organising biomolecular systems from the bottom up. This area of synthetic biology has also been recently strengthened by a new Royal Society Research Fellow, Dr Ross Anderson working on designer proteins.
