Aβ(1-42) is the highly pathologic isoform of amyloid-β, the peptide constituent of fibrils and neurotoxic oligomers involved in Alzheimer's disease. Recent studies on the structural features of Aβ in water have suggested that the system can be described as an ensemble of distinct conformational species in fast exchange. Here, we use replica exchange molecular dynamics (REMD) simulations to characterize the conformations accessible to Aβ42 in explicit water solvent, under the ff99SB force field. Monitoring the correlation between J-coupling((3)J(H(N))(H(α))) and residual dipolar coupling (RDC) data calculated from the REMD trajectories to their experimental values, as determined by NMR, indicates that the simulations converge towards sampling an ensemble that is representative of the experimental data after 60 ns/replica of simulation time. We further validate the converged MD-derived ensemble through direct comparison with (3)J(H(N))(H(α)) and RDC experimental data. Our analysis indicates that the ff99SB-derived REMD ensemble can reproduce the experimental J-coupling values with high accuracy and further provide good agreement with the RDC data. Our results indicate that the peptide is sampling a highly diverse range of conformations: by implementing statistical learning techniques (Laplacian eigenmaps, spectral clustering, and Laplacian scores), we are able to obtain an otherwise hidden structure in the complex conformational space of the peptide. Using these methods, we characterize the peptide conformations and extract their intrinsic characteristics, identify a small number of different conformations that characterize the whole ensemble, and identify a small number of protein interactions (such as contacts between the peptide termini) that are the most discriminative of the different conformations and thus can be used in designing experimental probes of transitions between such molecular states. This is a study of an important intrinsically disordered peptide system that provides an atomic-level description of structural features and interactions that are relevant during the early stages of the oligomerization and fibril nucleation pathways.
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