The Role of Binding Site Specificity in the Disaggregation of Aβ42 Fibrils through a Synthetic Paratope

Amyloid-{beta} (A{beta}) fibrils are the characteristic hallmark of Alzheimers 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 the A{beta} aggregation and disaggregate the preformed A{beta} fibrils. Here, we perform explicit molecular dynamics(MD) simulation to elucidate the molecular mechanism of disaggregation of preformed LS-shaped A{beta}42 protofibril with 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 A{beta}42 protofibril. However, binding of SP at the amyloidogenic core region (KLVFF) shows pronounced structural disruption of A{beta}42 protofibril. Our results show heavy loss of {beta} sheet content, dismantling of K28-A42 salt bridge, and destruction of key contacts in the hydrophobic cores of A{beta}42 protofibril in the presence of SP. We found the aromatic and hydrophobic residues of A{beta}42 protofibril participating primarily in the binding with SP. Also, we found that{pi} -{pi} stacking and hydrophobic interactions are the most dominant mode of interaction between SP and A{beta}42 protofibril. This work provides a detailed atomistic perspective on the A{beta}42 protofibril disaggregation mechanism with SP, and the findings can help develop more effective drugs for AD in the future.