Examining the Ensembles of Amyloid-β Monomer Variants and Their Propensities to Form Fibers Using an Energy Landscape Visualization Method

Abstract

The amyloid-β (Aβ) monomer, an intrinsically disordered peptide, is produced by the cleavage of the amyloid precursor protein, leading to Aβ-40 and Aβ-42 as major products. These two isoforms generate pathological aggregates, whose accumulation correlates with Alzheimer’s disease (AD). Experiments have shown that even though the natural abundance of Aβ-42 is smaller than that for Aβ-40, the Aβ-42 is more aggregation-prone compared to Aβ-40. Moreover, several single-point mutations are associated with early onset forms of AD. This work analyzes coarse-grained associative-memory, water-mediated, structure and energy model (AWSEM) simulations of normal Aβ-40 and Aβ-42 monomers, along with six single-point mutations associated with early onset disease. We analyzed the simulations using the energy landscape visualization method (ELViM), a reaction-coordinate-free approach suited to explore the frustrated energy landscapes of intrinsically disordered proteins. ELViM is shown to distinguish the monomer ensembles of variants that rapidly form fibers from those that do not form fibers as readily. It also delineates the amino acid contacts characterizing each ensemble. The results shed light on the potential of ELViM to probe intrinsically disordered proteins.

Influence of Ion Specificity and Concentration on the Conformational Transition of Intrinsically Disordered Sheep Prion Peptide

“…Therefore, it is necessary to take a different approach to analyze the complex multidimensional data generated from the MD simulation of IDPs. Recent reports on the dynamics of IDPs suggest that the principal component analysis [59,60] (PCA) or multidimensional scaling (MDS) [61] method is comparatively efficient to explain the statistical sampling of IDPs in the phase space. In the present work, we have considered the first two principal components i. e., PC1 and PC2 as the reaction coordinate to generate the free energy surface of the intrinsically disordered prion peptide in the presence of various salt solutions and depicted in Figure 7.…”

Effects of Familial Alzheimer’s Disease Mutations on the Folding Free Energy and Dipole–Dipole Interactions of the Amyloid β-Peptide

“…The mechanism by which mutations facilitate increased aggregation and a more severe form of AD is unknown. One recent simulation study applied a coarse-grain model to determine that Aβ 42 monomers are more prone to adopting fibril-like structures and that FAD mutations in Aβ 40 monomers reduce the free energy barriers between monomer and fibril-like structures . Thus, these mutations may play a role in modulating Aβ structure on the monomer level.…”

Effects of Familial Alzheimer’s Disease Mutations on the Folding Free Energy and Dipole-Dipole Interactions of the Amyloid β-Peptide

“…One recent simulation study applied a coarse-grain model to determine that Aβ 42 monomers are more prone to adopting fibril-like structures, and that FAD mutations in Aβ 40 monomers reduce the free energy barriers between monomer and fibril-like structures. 20 Thus, these mutations may play a role in modulating Aβ structure on the monomer level. tion.…”