Prof Frances Separovic, School of Chemistry, University of Melbourne
Most of us have felt the effect of a bee sting – but how does it actually work? The sting contains a peptide toxin, melittin, which kills cells by destroying the cell membrane. Understanding the mechanism by which melittin and other membrane-active peptides disrupt cell membranes may lead to new disease treatments and antibiotics. Modern nuclear magnetic resonance (NMR) techniques enable in situ study of the structure and dynamics of membrane molecules and the effects of toxins and antibiotics to be unravelled. Solid-state NMR studies of aligned phospholipid membranes have been used to determine the orientation and location of antimicrobial peptides obtained from Australian tree frogs and amyloid peptides from Alzheimer’s disease.
Although the detailed structure of these peptides in membranes is difficult to determine as they disrupt the membrane bilayer, their three dimensional structure and mechanism of action has been elucidated. A range of solid-state NMR techniques was used to determine the conformation and mobility of these membrane-active peptides in order to understand how they exert their biological effect that leads to the disruption of bacterial or neuronal membranes. The effect of the antimicrobial peptides on a variety of model membranes is strongly dependent on the lipid composition of the bilayer and correlates with selectivity for bacterial membranes and antibiotic activity. Likewise, the membrane interactions and structural changes of amyloid peptides from Alzheimer’s disease depend on the presence of cholesterol and metal ions, which have been implicated in the disease.