Energy Landscapes for the Aggregation of Aβ<sub>17-42</sub>.
Journal of the American Chemical Society
American Chemical Society
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Roeder, K., & Wales, D. (2018). Energy Landscapes for the Aggregation of Aβ<sub>17-42</sub>.. Journal of the American Chemical Society, 140 (11), 4018-4027. https://doi.org/10.1021/jacs.7b12896
The aggregation of the Aβ peptide (Aβ1-42) to form fibrils is a key feature of Alzheimer's disease. The mechanism is thought to be a nucleation stage followed by an elongation process. The elongation stage involves the consecutive addition of monomers to one end of the growing fibril. The aggregation process proceeds in a stop-and-go fashion, and may involve off-pathway aggregates, complicating experimental and computational studies. Here we present exploration of a well-defined region in the free and potential energy landscapes for the Aβ17-42 pentamer. We find that the ideal aggregation process agrees with the previously reported dock-lock mechanism. We also analyse a large number of additional stable structures located on the multifunnel energy landscape, which constitute kinetic traps. The key contributors to the formation of such traps are misaligned strong interactions, for example the stacking of F19 and F20, as well as entropic contributions. Our results suggest that folding templates for aggregation are a necessity, and that aggregation studies could employ such species to obtain a more detailed description of the process.
Humans, Peptide Fragments, Entropy, Molecular Dynamics Simulation, Amyloid beta-Peptides, Protein Aggregates
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External DOI: https://doi.org/10.1021/jacs.7b12896
This record's URL: https://www.repository.cam.ac.uk/handle/1810/275769
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/
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