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Molecular Determinants of A?42 Adsorption to Amyloid Fibril Surfaces.

ABSTRACT: The long lag times and subsequent rapid growth of Alzheimer's A?42 fibrils can be explained by a secondary nucleation step, in which existing fibril surfaces are able to nucleate the formation of new fibrils via an autocatalytic process. The molecular mechanism of secondary nucleation, however, is still unknown. Here we investigate the first step, namely, adsorption of the A?42 peptide monomers onto the fibril surface. Using long all-atom molecular simulations and an enhanced sampling scheme, we are able to generate a diverse ensemble of binding events. The resulting thermodynamics of adsorption are consistent with experiment as well as with the requirements for effective autocatalysis determined from coarse-grained simulations. We identify the key interactions stabilizing the adsorbed state, which are predominantly polar in nature, and relate them to the effects of known disease-causing mutations.

SUBMITTER: Bellaiche MMJ

PROVIDER: S-EPMC7507730 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Molecular Determinants of Aβ42 Adsorption to Amyloid Fibril Surfaces.

Bellaiche Mathias M J MMJ Best Robert B RB

The journal of physical chemistry letters 20181029 22

The long lag times and subsequent rapid growth of Alzheimer's Aβ42 fibrils can be explained by a secondary nucleation step, in which existing fibril surfaces are able to nucleate the formation of new fibrils via an autocatalytic process. The molecular mechanism of secondary nucleation, however, is still unknown. Here we investigate the first step, namely, adsorption of the Aβ42 peptide monomers onto the fibril surface. Using long all-atom molecular simulations and an enhanc ...[more]

PMID: 30371082

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Project description:Clinical studies have identified a correlation between type-2 diabetes mellitus and cognitive decrements en route to the onset of Alzheimer's disease (AD). Recent studies have established that post-translational modifications of the amyloid β (Aβ) peptide occur under hyperglycemic conditions; particularly, the process of glycation exacerbates its neurotoxicity and accelerates AD progression. In view of the assertion that macromolecular crowding has an altering effect on protein self-assembly, it is crucial to characterize the effects of hyperglycemic conditions via crowding on Aβ self-assembly. Toward this purpose, fully atomistic molecular dynamics simulations were performed to study the effects of glucose crowding on Aβ dimerization, which is the smallest known neurotoxic species. The dimers formed in the glucose-crowded environment were found to have weaker associations as compared to that of those formed in water. Binding free energy calculations show that the reduced binding strength of the dimers can be mainly attributed to the overall weakening of the dispersion interactions correlated with substantial loss of interpeptide contacts in the hydrophobic patches of the Aβ units. Analysis to discern the differential solvation pattern in the glucose-crowded and pure water systems revealed that glucose molecules cluster around the protein, at a distance of 5-7 Å, which traps the water molecules in close association with the protein surface. This preferential exclusion of glucose molecules and resulting hydration of the Aβ peptides has a screening effect on the hydrophobic interactions, which in turn diminishes the binding strength of the resulting dimers. Our results imply that physical effects attributed to crowded hyperglycemic environments are incapable of solely promoting Aβ self-assembly, indicating that further mechanistic studies are required to provide insights into the self-assembly of post-translationally modified Aβ peptides, known to possess aggravated toxicity, under these conditions.

Dataset Information

Molecular Determinants of A?42 Adsorption to Amyloid Fibril Surfaces.

Publications

Molecular Determinants of Aβ<sub>42</sub> Adsorption to Amyloid Fibril Surfaces.

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