Imaging CoE CI David Fairlie gives behind-the-scenes insight into his recently published study on helix nucleation, describing how the results could lead to a better understanding of infection and immunity.
All processes in the human body are driven by proteins interacting with other proteins. Chemists can synthesize these proteins in the laboratory but they are expensive to make and too structurally unstable and fragile to use as drugs. The UQ node of the Imaging CoE is working towards reducing proteins down to the world’s smallest helix structures. These will be cheap to make, chemically stable and can be modified to have the same biological activities as a protein.
David explains in a little more detail how his team are using the world’s smallest helix, that was in fact discovered by his group, as a building block to reconstruct pieces of proteins in these stable helical structures which otherwise cannot form in water.
Can you begin by outlining the short-term objectives of your study?
The short-term objectives are to understand the benefits and limitations of downsizing proteins into much smaller molecules that can structurally mimic the bioactive surfaces of proteins and thereby mimic the functions of proteins. In this study, the goal was to examine the world’s smallest helix (discovered by our group) for defects that might affect its ability to induce helicity when inserted into longer peptide chains. We found that it is very effective in coiling peptides into helical structures which otherwise do not form in water.
What about the long-term objectives and the wider impact of your discoveries?
The long-term objectives are to use these short water-stable helical structures to reproduce the biological activities of proteins (often hundreds to thousands of amino acids) in much smaller molecules – less than 20 amino acids. In the context of immunity, we can begin to create short helices that mimic or block protein-protein interactions that define infection, inflammatory and immunological processes leading to immunostimulants, immunosuppressants and anti-inflammatory agents to treat disease and to better understand the molecular basis of immunity.
Could you explain the relationship between helical sequences and protein-protein interactions?
Most biological processes are driven by interactions between proteins. Proteins are chains or sequences of amino acids that are folded into specific 3D structures which are essential for protein functions. About one-third of the structure of a protein is composed of helix structures and, when on the surface of a protein, the helix is often the part that interacts with another protein.
What is the significance of optimising small peptide mimics of biologically important protein α-helixes?
The length of most protein helices that interact with another protein is 1-4 helix coils (helix turns) or less than 20 amino acids. Such short sequences of amino acids corresponding to helical segments of a protein are called peptides. In water, these short peptides unwind – and, when away from the stabilising environment inside a protein where they are packed together, they are no longer helical and thus do not show the biological properties of proteins.
To maintain protein-like biological activities of these very short chains of amino acids, researchers have been seeking ways to stabilise short alpha helical peptides that could have potent biological functions like proteins.
Why did you choose to investigate helix nucleation in water?
We discovered how to stabilise one turn of an alpha helix in water using just 5 amino acids. This is the shortest known alpha helix and it is highly stable, even in conditions that fully unwind helices in proteins. We decided to use this alpha helical turn as a template or scaffold within longer peptides to help them fold in water. This enables peptides of 5-25 amino acids to become helical structures in water.
How can this knowledge help us better understand disease and infection?
By stabilising an alpha helix in a short peptide of less than 20 amino acids, we can potentially recreate the bioactive helical surfaces of proteins in much smaller, cheaper-to-manufacture and more water-stable molecules. These could then be used as probes or drug candidates to interrogate mechanisms of infection and disease development – and even, in the future, to treat disease.