Distinct thermodynamic signature of oligomer generation in the aggregation of the amyloid-β peptide

Mapping energy landscapes has proved to be a powerful tool for studying reaction mechanisms. Many complex biomolecular assembly processes, however, have remained challenging to access using this approach, including the aggregation of peptides and proteins into amyloid fibrils implicated in various disorders. Here we generalize the strategy used to probe energy landscapes in protein folding to determine the activation energies and entropies that characterise each of the molecular steps in the aggregation of the amyloid-β peptide (Aβ42), which is associated with Alzheimer’s disease. Our results reveal that interactions between monomeric Aβ and amyloid fibrils during fibril-dependent nucleation fundamentally reverse the thermodynamic signature of this process relative to primary nucleation, even though both processes generate aggregates from soluble peptides. By mapping the energetic and entropic contributions along the reactive trajectories, we show that the catalytic efficiency of Aβ42 fibril surfaces results from the enthalpic stabilisation of adsorbing peptides in conformations amenable to nucleation, driving a dramatic lowering of the activation energy barrier for nucleation.