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.
Highlights
Aggregates of the amyloid-β (Aβ) protein are a key feature of Alzheimer’s disease,[1−4] and their formation and properties have been the subject of many studies.[5,6] the exact mechanism of pathogenicity is still uncertain, with active research surrounding every aspect of the underlying biochemistry
It is thought that there are three key processes in fibril formation, namely, primary and secondary nucleation, which both result in the formation of protofibrils that subsequently grow by an elongation process.[7,8]
We report a detailed description of possible kinetic traps for the aggregation process and consider the implications for studies of protein aggregation in general
Summary
Aggregates of the amyloid-β (Aβ) protein are a key feature of Alzheimer’s disease,[1−4] and their formation and properties have been the subject of many studies.[5,6] the exact mechanism of pathogenicity is still uncertain, with active research surrounding every aspect of the underlying biochemistry. Aggregates of the 42-residue Aβ peptide (Aβ1−42) lead to the formation of amyloid fibrils, which appear to be a necessary condition for Alzheimer’s to develop. It has been found that there are a number of pathways to fibrils via primary aggregation, as well as off-pathway aggregation processes, leading to kinetically trapped oligomeric structures.[11−14] we need to understand the structural ensembles the oligomers and fibrils inhabit, the pathways connecting oligomers to fibrils, and the formation of offpathway oligomers
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