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Exploring the aggregation free energy landscape of the amyloid-β protein (1–40)
Contributed by Peter G. Wolynes, August 17, 2016 (sent for review July 28, 2016; reviewed by William A. Eaton and Angel E. Garcia)

Significance
Protein aggregation and amyloid formation seem to be at the heart of the pathology of multiple neurodegenerative diseases, including Alzheimer’s disease.
Abstract
A predictive coarse-grained protein force field [associative memory, water-mediated, structure, and energy model for molecular dynamics (AWSEM)-MD] is used to study the energy landscapes and relative stabilities of amyloid-β protein (1–40) in the monomer and all of its oligomeric forms up to an octamer. We find that an isolated monomer is mainly disordered with a short α-helix formed at the central hydrophobic core region (L17-D23). A less stable hairpin structure, however, becomes increasingly more stable in oligomers, where hydrogen bonds can form between neighboring monomers. We explore the structure and stability of both prefibrillar oligomers that consist of mainly antiparallel β-sheets and fibrillar oligomers with only parallel β-sheets. Prefibrillar oligomers are polymorphic but typically take on a cylindrin-like shape composed of mostly antiparallel β-strands. At the concentration of the simulation, the aggregation free energy landscape is nearly downhill. We use umbrella sampling along a structural progress coordinate for interconversion between prefibrillar and fibrillar forms to identify a conversion pathway between these forms. The fibrillar oligomer only becomes favored over its prefibrillar counterpart in the pentamer where an interconversion bottleneck appears. The structural characterization of the pathway along with statistical mechanical perturbation theory allow us to evaluate the effects of concentration on the free energy landscape of aggregation as well as the effects of the Dutch and Arctic mutations associated with early onset of Alzheimer’s disease.
Footnotes
- ↵1To whom correspondence should be addressed. Email: pwolynes{at}rice.edu.
Author contributions: W.Z. and P.G.W. designed research; W.Z. performed research; W.Z., M.-Y.T., and M.C. contributed new reagents/analytic tools; W.Z., M.-Y.T., and P.G.W. analyzed data; and W.Z. and P.G.W. wrote the paper.
Reviewers: W.A.E., National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; and A.E.G., Los Alamos National Laboratory.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1612362113/-/DCSupplemental.
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