On the Protein Folding Problem

Proteins are the biological workhorses that carry out vital functions in living cells. Before they can carry out their required functions, the proteins must fold into a complex three-dimensional structure but the underlying factors that perform this folding process remain unclear. Although the steps leading to protein folding are fast and highly efficient, things sometimes go wrong. This can have harmful consequences, as the incorrect folding of proteins is thought to be the cause of many diseases, such as Alzheimer's disease and certain types of cancer. We propose here to build an instrument that will enable the systematic study of the dynamics of protein folding over a very wide temporal range. A key feature of the new instrument will involve a high-pressure cell that allows conformational motion to be controlled by varying frictional forces. The instrument will be used to follow large-scale unfolding of a short protein triggered by breaking a disulphide bond. This study should expose the mechanism and thermodynamics associated with the unfolding and refolding processes. Subsequent work should help unravel the role of metal ions in promoting Alzheimer's disease.