Making peptides with split personalities
22 October 2006
Understanding the link between the chemistry of a protein chain (its sequence) and its 3D structure is known as the protein-folding problem.
Almost all of these functions depend on the proteins involved adopting defined 3D structures. For experimental reasons, one tends to view proteins in their native, static structures. However, many of the listed functions are not possible without proteins undergoing structural changes. That is, proteins often switch shape in response to specific stimuli. In turn, such changes pass-on information, or otherwise express the protein’s function. For example, the ability of haemoglobin to pick up oxygen near the lungs, transport it through the arteries, and release it at working tissue (cells, muscle etc) depends on the protein being able to adopt two different structures with different affinities for oxygen. Structural changes in proteins can also cause problems as in Alzheimer’s disease and BSE, where small, soluble proteins are converted to large insoluble aggregates known as amyloid.
Peptides are essentially shorter versions of proteins.
Through a BBSRC grant Woolfson’s group has extended and challenged protein-folding studies by attempting to capture protein-structure switching in tractable peptide models, which they have designed from first principles. Peptides are essentially shorter versions of proteins. Whilst peptides often do not display the richness of structure, function or stability shown by whole proteins, they are experimentally more accessible, and, potentially, easier to describe and understand. Indeed, one of the long-term aims of the group is to help understand structural transitions in natural proteins by studying peptides. In addition, designed molecules such as peptides have potential applications as components of tiny devices in the emerging field of bionanotechnology.
The studies performed on the grant centred on three designed peptide systems. The first aimed to take a small, but structurally defined motif known as a leucine zipper—which comprises two protein chains wrapped around each other like a rope—and make changes to its sequence to encourage it to switch to amyloid-like aggregates. At the time of writing the original proposal, this appeared to be a good system for advancing these ideas. However, during the early stages of the grant it became clear that this system was fraught with difficulties, and the group could not obtain reproducible, and therefore reliable, data. As a result, they could not pursue their original objective, which was to understand the underlying sequence rules for switching to amyloid-like structures important in disease. Therefore, they turned to the design of two other switches. In both cases, one of the structural states was the leucine zipper. The other states were (1) a simpler structure that is bent double like a hairpin, and (2) a more-complex architecture with additional structural features and that help proteins bind the metal zinc. The aim of the latter, which the group spent the most time developing, was to achieve switching in a subtle, controllable and reversible way by the addition and removal of zinc.
After the initial set-backs, the work proceeded extremely well: the group has published its findings in leading peer-reviewed academic journals and has also filed patents on their designs. One possible long-term application of their protein switches is to use them as the molecular (or nanoscale) components in devices that sense changes in conditions in biological fluids, which could lead to biomedical applications.