Department of Chemistry

Biophysical and structural studies of protein folding

Protein folding is an increasingly important field in biomedical research. We combine the tools of physical chemistry, protein engineering, computer simulation and structural biology to investigate the folding process at the molecular level. We are concentrating on four specific research areas:

The folding of related proteins: By comparing the folding of a number of related proteins from large structural families we can investigate the relationship between amino acid sequence and topology and protein stability.
The folding of multidomain proteins: Most proteins consist of a number of independently folding domains. How do domain:domain interactions modulate the properties of the protein?

How pathogenic mutations cause disease: Most pathogenic mutations result in protein instability. We are developing methods to predict how mutations affect the biophysical properties of proteins and relating these to the severity of disease.
Mechanical unfolding studies: Many proteins in the body (such as muscle proteins) may be subject to significant mechanical stress. We have developed single molecule force measurements to investigate the way proteins unfold when subject to force. Combined with protein engineering and computer simulation we can investigate the unfolding at the molecular level.

Selected Publications

• Nickson, A.A. and Clarke, J. (2010) What lessons can be learned from studying the folding of homologous proteins? Methods in press doi:10.1016/j.ymeth.2010.06.003
• Wensley, B.G., Batey, S., Bone, F.A.C., Chan, Z.M., Tumelty, N.R., Steward, A., Kwa, L.G., Borgia, A. and Clarke, J. (2010) Experimental evidence for a frustrated energy landscape in a 3-helix bundle protein family. Nature 463, 685-689
• Forman, J.R., Yew, Z.T., Qamar, S., Sandford, R.N., Paci, E. and Clarke, J. (2009) Non- native interactions are critical for mechanical strength in PKD domains. Structure 17, 1582– 1590
• Steward, A.S., McDowell, G.S, and Clarke, J. (2009) Topology is the principle determinant in the folding of a complex all-alpha Greek key Death Domain from Human FADD. J. Mol. Biol. 389, 935-940