Molecular Dynamic simulations of Aβ42 dimers with solid-state NMR restraints capture the key structural motifs in Aβ42 fibrillation pathways

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 simulated the conformational evolution of Aβ42 dimers in solution and in membrane-like environment to explore the folding of Aβ42 along fibrillation. The molecular dynamics (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 those motifs are also the stabilizing agents in the mature fibrils judged by the energy contribution. Our results also indicated that the peptide association with membrane bilayers could modulate the structural evolution pathways towards 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.