Mutations alter the geometry and mechanical properties of Alzheimer's Aβ(1-40) amyloid fibrils.
The identification of more efficient therapies for defeating severe degenerative diseases like Alzheimer's is a major goal of drug discovery research. Realizing this ambitious goal will likely require a series of molecular insights that shed light on the fundamental mechanisms that drive the formation, growth, stability, and toxicity of Aβ(1-40) amyloid fibrils, one of the most abundant species found in affected brain tissues and potentially a major player in the progression of Alzheimer's disease. Amyloid fibrils feature a highly ordered and dense network of hydrogen bonds, a universal feature of all amyloid structures, which is realized by a highly regular stacking of small β-units that are each stabilized by an intrapeptide salt bridge. Here we report a series of molecular dynamics simulations of large-scale amyloid fibrils with local mutations that result in the disruption of the key intrapeptide salt bridge. We demonstrate that mutations, through alterations in the nature of the salt bridge, have a significant effect on the geometry and mechanical properties of the amyloid fibril. We specifically observe a severe decrease in amyloid fibril periodicity (the period length) of up to 43%, and extreme variations of the Young's modulus (a measure of the fibril's mechanical stiffness) of up to 154%. These results confirm that, while on one hand side chains are not involved in the formation of the β-strands composing the inner core of the amyloid structure, their presence, size, and interactions can be crucial in determining the larger-scale properties of amyloid fibrils. Our results imply that interactions mediated by side chains could be a potential target for novel approaches to drug design and the development of molecular therapies for amyloid disorders such as Alzheimer's disease, through the chemical deactivation of key functional groups that are responsible for promoting the growth of the fibrils, for promoting their chemical and mechanical stability, and for furthering their aggregation in amyloid plaques.
Paparcone
Raffaella
R
Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139-4301, USA.
Pires
Matthew A
MA
Buehler
Markus J
MJ
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017433:Protein Structure, Secondary
D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)