Role of Binding Site Specificity in the Disaggregation of Aβ₄₂ Fibrils via Synthetic Paratope

Amyloid-β (Aβ) fibrils are the characteristic hallmark of Alzheimer's disease (AD), and most drug development approaches for AD are focused on preventing and reversing the formation of these fibrillar aggregates. Previous studies show that synthetic antibodies have demonstrated great potential to inhibit Aβ aggregation and disaggregate the preformed Aβ fibrils. Here, we perform explicit molecular dynamics (MD) simulation to elucidate the molecular mechanism of disaggregation of a preformed LS-shaped Aβ₄₂ protofibril by a flexible, hairpin-like synthetic paratope (SP), which, in a recent experimental study, has shown promising results. Our simulations demonstrate various potential binding sites for SP on the Aβ₄₂ protofibril. However, binding of SP at the amyloidogenic core region (KLVFF) shows pronounced structural disruption of the Aβ₄₂ protofibril. Our results show heavy loss of β-sheet content, dismantling of the K28-A42 salt bridge, and destruction of key contacts in the hydrophobic cores of the Aβ₄₂ protofibril in the presence of SP. We found the aromatic and hydrophobic residues of Aβ₄₂ protofibril participating primarily in the binding with SP. Also, we found that π-π stacking and hydrophobic interactions are the most dominant modes of interaction between SP and the Aβ₄₂ protofibril. This work provides a detailed atomistic perspective on the Aβ₄₂ protofibril disaggregation mechanism with SP, and the findings can help in the development of more effective drugs for AD in the future.