Oligomer Formation by Physiologically Relevant C-Terminal Isoforms of Amyloid β-Protein

Alzheimer's disease (AD) is a neurological disorder associated with amyloid beta-protein (A beta) assembly into toxic oligomers. In addition to the two predominant alloforms, A beta(1-40) and A beta(1-42), other C-terminally truncated A beta peptides, including A beta(1-38) and A beta(1-43), are produced in the brain. Here, we use discrete molecular dynamics (DMD) and a four-bead protein model with amino acid-specific hydropathic interactions, DMD4B-HYDRA, to examine oligomer formation of A beta(1-38), A beta(1-40), A beta(1-42), and A beta(1-43). Self-assembly of 32 unstructured monomer peptides into oligomers is examined using 32 replica DMD trajectories for each of the four peptides. In a quasi-steady state, A beta(1-38) and A beta(1-40) adopt similar unimodal oligomer size distributions with a maximum at trimers, whereas A beta(1-42) and A beta(1-43) oligomer size distributions are multimodal with the dominant maximum at trimers or tetramers, and additional maxima at hexamers and unidecamers (for A beta(1-42)) or octamers and pentadecamers (for A beta(1-43)). The free energy landscapes reveal isoform- and oligomer-order specific structural and morphological features of oligomer ensembles. Our results show that oligomers of each of the four isoforms have unique features, with A beta(1-42) alone resulting in oligomers with disordered and solvent-exposed N-termini. Our findings help unravel the structure-function paradigm governing oligomers formed by various A beta isoforms.