We find eight mutations, spread out over the full fibril structure; Y6A, Y8A, L11A, I22A, I29A, V32A, I53A and V74A, are highly destabilizing ([∆∆G A-U ] > 5 kJ mol -1 ) (Figure ). Most of these mutations face the hydrophobic core or interfilament face, consistent with the large effect . The magnitude of destabilization upon V32A-mutation is unexpected, as the residue side chain faces the solvent. It is striking to consider the V74A and L40V mutation, due to their structural proximity at the hydrophobic filament interface and similar chemistry, but vastly different effects on the fibril stability.