Stabilization Mechanism for a Nonfibrillar Amyloid β Oligomer Based on Formation of a Hydrophobic Core Determined by Dissipative Particle Dynamics.

Abstract

Neurotoxicity caused by nonfibrillar amyloid β (Aβ) oligomers in the brain is suggested to be associated with the onset of Alzheimer's disease (AD). Elucidating the structural features of Aβ oligomers is critical for promoting drug discovery research for AD. One of the Aβ oligomers, known as Aβ*56, is a dodecamer that impairs memory when injected into healthy rats, suggesting that Aβ*56 may contribute to cognitive deficits in AD patients. Another dodecamer structure, formed by 20-residue peptide segments derived from the Aβ peptide (Aβ17-36), has been revealed by X-ray crystallography. The structure of the Aβ17-36 dodecamer is composed of trimer units and shows the oligomer antibody A11 reactivity, which are characteristic of Aβ*56, indicating that Aβ*56 and the Aβ17-36 dodecamer share a similar structure. However, the structure of the C-terminal regions (Aβ37-42) remains unclear. The C-terminal region, which is abundant in hydrophobic residues, is thought to play a key role in stabilizing the oligomer structure by forming a hydrophobic core. In this study, we employed dissipative particle dynamics, a coarse-grained simulation method with soft core potentials, utilizing the crystal structure information to unravel Aβ dodecamer structures with C-terminal regions. The simulation results were validated by the reported experimental data. Hence, an analysis of the simulation results can provide structural insights into Aβ oligomers. Our simulations revealed the stabilization mechanism of the dodecamer structure at the molecular level. We showed that C-terminal regions spontaneously form a hydrophobic core in the central cavity, contributing to stabilizing the dodecamer structure. Furthermore, four consecutive hydrophobic residues in the C-terminal region (i.e., Val39-Ala42) are important for core formation.