Molecular Dynamics Simulations of Aβ ₄₂ Dimers with Solid-State NMR Restraints Capture the Key Structural Motifs in Aβ ₄₂ Fibrillation Pathways

High Resolution Image Download MS PowerPoint Slide Formation of the β-amyloid (Aβ) plaques is a pathological hallmark of Alzheimer’s disease (AD) and is believed to be a primary cause of dementia in elderly individuals. In the present work, we performed molecular dynamics (MD) simulations on the conformational evolution of Aβ 42 dimers in solution and in a membrane-like environment to explore the folding of Aβ 42 during fibrillation. Particularly, the MD simulation was steered by experimental internuclear distance restraints obtained using solid-state nuclear magnetic resonance (ssNMR) spectroscopy. Our results revealed that several hydrophobic and polar motifs within the Aβ 42 sequence played key roles in the early-stage nucleation process of fibrillation, and these motifs are also the stabilizing agents in the mature fibrils, as judged by the energy contribution. Our results also indicated that the membrane-binding of small Aβ oligomers could modulate their structural evolution pathways toward fibrillation. These findings contributed to a better understanding of the molecular-level structural polymorphisms inherent to Aβ 42 fibrils. Further, the current work demonstrated that the combination of MD simulations with ssNMR-based experimental restraints provided a reliable method for studying structural changes of Aβ.