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

Abstract

Alzheimer’s disease (AD) is a neurological disorder associated with amyloid (Formula presented.) -protein (A (Formula presented.)) assembly into toxic oligomers. In addition to the two predominant alloforms, A (Formula presented.) and A (Formula presented.), other C-terminally truncated A (Formula presented.) peptides, including A (Formula presented.) and A (Formula presented.), 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 (Formula presented.), A (Formula presented.), A (Formula presented.), and A (Formula presented.). 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 (Formula presented.) and A (Formula presented.) adopt similar unimodal oligomer size distributions with a maximum at trimers, whereas A (Formula presented.) and A (Formula presented.) oligomer size distributions are multimodal with the dominant maximum at trimers or tetramers, and additional maxima at hexamers and unidecamers (for A (Formula presented.)) or octamers and pentadecamers (for A (Formula presented.)). 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 (Formula presented.) 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 (Formula presented.) isoforms.