Journal
NATURE CHEMISTRY
Volume 10, Issue 5, Pages 523-531Publisher
NATURE RESEARCH
DOI: 10.1038/s41557-018-0023-x
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Funding
- Schiff Foundation
- St John's College, Cambridge
- Royal Physiographic Society
- Research School FLAK of Lund University
- Swedish Research Council
- Linneaus Centre Organizing Molecular Matter
- Crafoord Foundation
- Alzheimerfonden
- European Research Council
- NanoLund
- Knut and Alice Wallenberg Foundation
- Peterhouse, Cambridge
- Swiss National Science Foundation
- Magdalene College, Cambridge
- Leverhulme Trust
- Royal Society
- Academy of Medical Sciences
- Wellcome Trust
- Centre for Misfolding Diseases
- Academy of Medical Sciences (AMS) [SBF002\\1087] Funding Source: researchfish
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Mapping free-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 a range of disorders. Here, we generalize the strategy used to probe free-energy landscapes in protein folding to determine the activation energies and entropies that characterize each of the molecular steps in the aggregation of the amyloid-beta peptide (A beta 42), which is associated with Alzheimer's disease. Our results reveal that interactions between monomeric A beta 42 and amyloid fibrils during fibril-dependent secondary 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 reaction trajectories, we show that the catalytic efficiency of A beta 42 fibril surfaces results from the enthalpic stabilization of adsorbing peptides in conformations amenable to nucleation, resulting in a dramatic lowering of the activation energy for nucleation.
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