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Updated: May 10, 2026
Characterizing Individual Protein Aggregates by Infrared Nanospectroscopy and Atomic Force Microscopy
Published on: September 12, 2019
Aβ monomers transiently sample oligomer and fibril-like configurations: ensemble characterization using a combined
David J Rosenman1, Christopher R Connors, Wen Chen
1Department of Biology, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA.
Abstract:
Amyloid β (Aβ) peptides are a primary component of fibrils and oligomers implicated in the etiology of Alzheimer's disease (AD). However, the intrinsic flexibility of these peptides has frustrated efforts to investigate the secondary and tertiary structure of Aβ monomers, whose conformational landscapes directly contribute to the kinetics and thermodynamics of Aβ aggregation. In this work, de novo replica exchange molecular dynamics (REMD) simulations on the microseconds-per-replica timescale are used to characterize the structural ensembles of Aβ42, Aβ40, and M35-oxidized Aβ42, three physiologically relevant isoforms with substantially different aggregation properties. J-coupling data calculated from the REMD trajectories were compared to corresponding NMR-derived values acquired through two different pulse sequences, revealing that all simulations converge on the order of hundreds of nanoseconds-per-replica toward ensembles that yield good agreement with experiment. Though all three Aβ species adopt highly heterogeneous ensembles, these are considerably more structured compared to simulations on shorter timescales. Prominent in the C-terminus are antiparallel β-hairpins between L17-A21, A30-L36, and V39-I41, similar to oligomer and fibril intrapeptide models that expose these hydrophobic side chains to solvent and may serve as hotspots for self-association. Compared to reduced Aβ42, the absence of a second β-hairpin in Aβ40 and the sampling of alternate β topologies by M35-oxidized Aβ42 may explain the reduced aggregation rates of these forms. A persistent V24-K28 bend motif, observed in all three species, is stabilized by buried backbone to side-chain hydrogen bonds with D23 and a cross-region salt bridge between E22 and K28, highlighting the role of the familial AD-linked E22 and D23 residues in Aβ monomer folding. These characterizations help illustrate the conformational landscapes of Aβ monomers at atomic resolution and provide insight into the early stages of Aβ aggregation pathways.
Insights
This study used molecular dynamics simulations to reveal the complex structures of amyloid beta (Aβ) monomers, offering new insights into Alzheimer
Area of Science:
- Biochemistry
- Molecular Biology
- Neuroscience
Background:
- Amyloid beta (Aβ) peptides, particularly Aβ42 and Aβ40, are central to Alzheimer's disease (AD) pathogenesis.
- The conformational flexibility of Aβ monomers hinders understanding of their aggregation mechanisms.
- Investigating monomer structure is crucial for elucidating the kinetics and thermodynamics of Aβ aggregation.
Purpose of the Study:
- To characterize the structural ensembles of physiologically relevant Aβ isoforms (Aβ42, Aβ40, M35-oxidized Aβ42).
- To explore the conformational landscapes of Aβ monomers at atomic resolution.
- To provide insights into the early stages of Aβ aggregation pathways.
Main Methods:
- De novo replica exchange molecular dynamics (REMD) simulations on the microseconds-per-replica timescale.
- Calculation of J-coupling data from REMD trajectories for comparison with experimental NMR data.
- Analysis of structural convergence and comparison across different Aβ isoforms.
Main Results:
- Simulations achieved convergence, yielding good agreement with experimental NMR data.
- All three Aβ isoforms adopt heterogeneous yet more structured ensembles than previously observed.
- Identified key structural motifs including antiparallel β-hairpins and a persistent V24-K28 bend, stabilized by specific interactions.
Conclusions:
- The structural differences, such as the absence of a second β-hairpin in Aβ40 and alternate topologies in oxidized Aβ42, may explain their distinct aggregation rates.
- Specific residues (E22, D23) and interactions play a critical role in Aβ monomer folding.
- Detailed characterization of Aβ monomer conformational landscapes provides a foundation for understanding early aggregation events in Alzheimer's disease.
