Aβ Monomers Transiently Sample Oligomer and Fibril-Like Configurations: Ensemble Characterization Using a Combined MD/NMR Approach

Amyloid beta (A beta) 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 A beta monomers, whose conformational landscapes directly contribute to the kinetics and thermodynamics of A beta 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 A beta 42, A beta 40, and M35-oxidized A beta 42, 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 A beta species adopt highly heterogeneous ensembles, these are considerably more structured compared to simulations on shorter timescales. Prominent in the C-terminus are antiparallel beta-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 A beta 42, the absence of a second beta-hairpin in A beta 40 and the sampling of alternate 13 topologies by M35-oxidized A beta 42 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 A beta monomer folding. These characterizations help illustrate the conformational landscapes of A beta monomers at atomic resolution and provide insight into the early stages of A beta aggregation pathways. (C) 2013 Elsevier Ltd. All rights reserved.