Energy Landscapes for the Aggregation of Aβ17-42

Journal of the American Chemical Society
Konstantin Röder, David J Wales

Abstract

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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Citations

Feb 25, 2021·Physical Chemistry Chemical Physics : PCCP·Konstantin Röder
Jul 10, 2021·The Journal of Chemical Physics·S R NateshE J Haddadian
Apr 12, 2019·Chemical Reviews·Ioana M Ilie, Amedeo Caflisch
Apr 28, 2020·The Journal of Physical Chemistry. B·Daniel J SharpeDavid J Wales
Apr 20, 2019·The Journal of Physical Chemistry Letters·Sneha Menon, Neelanjana Sengupta
Mar 4, 2020·The Journal of Physical Chemistry. B·James A Ross-NaylorMark J Biggs
May 17, 2019·The Journal of Physical Chemistry. B·Gianmarc GrazioliCarter T Butts
Jul 18, 2019·ACS Chemical Neuroscience·Hyunsung ChoiSungsoo Na
May 18, 2019·ACS Chemical Neuroscience·Yuechuan XuPeter G Vekilov
Nov 16, 2018·The Journal of Physical Chemistry. B·Jerelle A Joseph, David J Wales

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