Energy
Landscapes for the Aggregation of Aβ17–42
Version 2 2018-03-23, 23:44
Version 1 2018-03-08, 17:36
Posted on 2018-03-23 - 23:44
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 analyze 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.
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Röder, Konstantin; Wales, David J. (2018). Energy
Landscapes for the Aggregation of Aβ17–42. ACS Publications. Collection. https://doi.org/10.1021/jacs.7b12896
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