Abstract
BackgroundMisfolding and self-assembly of Amyloid-β (Aβ) peptides into amyloid fibrils is pathologically linked to the development of Alzheimer's disease. Polymorphic Aβ structures derived from monomers to intermediate oligomers, protofilaments, and mature fibrils have been often observed in solution. Some aggregates are on-pathway species to amyloid fibrils, while the others are off-pathway species that do not evolve into amyloid fibrils. Both on-pathway and off-pathway species could be biologically relevant species. But, the lack of atomic-level structural information for these Aβ species leads to the difficulty in the understanding of their biological roles in amyloid toxicity and amyloid formation.Methods and FindingsHere, we model a series of molecular structures of Aβ globulomers assembled by monomer and dimer building blocks using our peptide-packing program and explicit-solvent molecular dynamics (MD) simulations. Structural and energetic analysis shows that although Aβ globulomers could adopt different energetically favorable but structurally heterogeneous conformations in a rugged energy landscape, they are still preferentially organized by dynamic dimeric subunits with a hydrophobic core formed by the C-terminal residues independence of initial peptide packing and organization. Such structural organizations offer high structural stability by maximizing peptide-peptide association and optimizing peptide-water solvation. Moreover, curved surface, compact size, and less populated β-structure in Aβ globulomers make them difficult to convert into other high-order Aβ aggregates and fibrils with dominant β-structure, suggesting that they are likely to be off-pathway species to amyloid fibrils. These Aβ globulomers are compatible with experimental data in overall size, subunit organization, and molecular weight from AFM images and H/D amide exchange NMR.ConclusionsOur computationally modeled Aβ globulomers provide useful insights into structure, dynamics, and polymorphic nature of Aβ globulomers which are completely different from Aβ fibrils, suggesting that these globulomers are likely off-pathway species and explaining the independence of the aggregation kinetics between Aβ globulomers and fibrils.
Highlights
Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disease characterized by extracellular deposition of bamyloid (Ab) as senile plaques and intracellular accumulation of aggregated neurofibrillary tau tangles [1] in human brain
Our computationally modeled Ab globulomers provide useful insights into structure, dynamics, and polymorphic nature of Ab globulomers which are completely different from Ab fibrils, suggesting that these globulomers are likely off-pathway species and explaining the independence of the aggregation kinetics between Ab globulomers and fibrils
Model construction there is no atomic structure of Ab globulomers available to date, experimental characterization of Ab1–42 globulomers by Barghorn et al [11,15] and Yu et al [28] has shown that (i) Ab globulomers mainly consists of 12 Ab monomers; (ii) Ab globulomers display a circular shape with heights of 4–6 nm by AFM images; and (iii) Ab globulomers form a hydrophobic inner core via hydrophobic C-terminal b-strands, while hydrophilic N-terminal b-strands are exposed to bulk solvent
Summary
Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disease characterized by extracellular deposition of bamyloid (Ab) as senile plaques and intracellular accumulation of aggregated neurofibrillary tau tangles [1] in human brain. Ab1–40 is a more abundant species, whereas Ab1–42 is more neurontoxic species Both Ab peptides have an extracellular hydrophilic N-terminus (residues 1– 28) and a membrane-inserted C-terminus region (residues 29–40 or 29–42) [3]. Accumulating evidence has shown that soluble Ab oligomers are more neurotoxic than Ab fibrils [5]. Studies of transgenic mouse models demonstrated that significant neuronal injury occurred before the appearance of amyloid plaques [9,10]. Some aggregates are on-pathway species to amyloid fibrils, while the others are off-pathway species that do not evolve into amyloid fibrils. Both on-pathway and offpathway species could be biologically relevant species. The lack of atomic-level structural information for these Ab species leads to the difficulty in the understanding of their biological roles in amyloid toxicity and amyloid formation
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