Molecular Dynamics Simulations of Aβ₄₂ Dimers with Solid-State NMR Restraints Capture the Key Structural Motifs in...

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 Aβ₄₂ dimers in solution and in a membrane-like environment to explore the folding of Aβ₄₂ 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 Aβ₄₂ 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 Aβ₄₂ 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.