Amyloid Formation in Antimicrobial Peptides: Exploring the Role of Helical Intermediates

Protein self-assembly into fibrillar structures, called amyloids, is associated with more than fifty human diseases. The mechanism of amyloid formation is still unclear; however, helical intermediates forming in the early stages of fibrillation are reported as toxic species. Interestingly, antimicrobial peptides also form helix-rich aggregates that can kill bacteria. In this thesis, amyloid-forming antimicrobial peptides derived from an Australian toadlet are used to gain mechanistic insights into helical intermediate formation in solutions and membrane-mimetic environments. Using a combination of molecular dynamics simulations and biophysical experiments, this thesis explores the crucial role of electrostatic and hydrophobic interactions in the formation of helical intermediates on the pathway to amyloid formation.