My research in collaboration with Dr. Peter Davies' lab has involved the use of X-ray crystallography and molecular modelling to study both the calpain family of enzymes and ice-binding proteins.
Calpains are a family of cysteine proteases that depend on the presence of Ca2+ to allow them to adopt an active conformation. We are studying their structures to try to understand the details of this activation process. We use X-ray crystallography and modelling to determine structures of the enyzme in combination with substrates and inhibitors for use in structure-based inhibitor design. Specific inhibitors may be useful in further research studies and as potential lead compounds for the development of pharmaceuticals for the treatment after ischemic reperfusion events.
Antifreeze proteins (AFPs) are one class of ice-binding proteins that bind to the surfaces of ice crystals and inhibit their growth at subzero temperatures, thereby protecting the organism from freezing damage. We have hypothesized that AFPs bind to ice by first ordering water molecules at the protein's surface to be in an ice-like array. In order to explore this idea, we are using X-ray crystallography and homology modelling along with site-directed mutagenesis to examine the ordering of water molecules around the proteins' surfaces. Another class of ice-binding proteins are those that nucleate the formation of ice (ice-nucleating proteins, INPs) that appear to differ from AFPs predominantly by the size of their ice-binding site. We are attempting to explore this relationship by engineering INPs from AFPs and vice versa.