ABSTRACT

Aggregation of amyloid β peptides (AβP) forming fibrils and senile plaques is associated with numerous neurodegenerative disorders such as Alzheimer’s disease (AD). While there is no cure for AD, there is a possibility to retard and prevent the impairment. Inhibiting or interfering the aggregation of Aβ using fullerenes has shown to be a promising strategy to treat AD. The hydrophobic nature of fullerenes compromises its interaction with living cells inducing toxicity; thus, it is necessary to functionalize the molecule promoting its water solubility. In this study, we evaluate the structural and dynamical properties of six diethyl malonate C₆₀ fullerene adducts and its corresponding sodium salts in aqueous solution by molecular dynamics simulations. By means of radial distribution functions, hydrogen bond counting, density profiles, and solvent-accessible surface area, we demonstrate that the sodium malonate fullerene adducts have higher hydration ability while the corresponding diethyl malonate adducts show a hydrophobic tendency, forming self-aggregates. Additionally, we calculate the density profiles of ternary systems including amyloid β peptide 1–42 (AβP₄₂) monomers and found that bis-, tris-, tetra-, and pentaadducts of C₆₀ with disodium malonate addends interact with amyloid molecules, blocking partially their self-aggregation. These data support the understanding of previous reports that indicated the efficiency of sodium malonate fullerene as inhibitors of AβP aggregation. Additionally, we performe measurements in vitro by dynamic light scattering and found that fullerene aggregation is independent of incubation time.

摘要

形成原纤维和老年斑的淀粉样β肽（AβP）的聚集与许多神经退行性疾病例如阿尔茨海默氏病（AD）有关。虽然无法治愈AD，但有可能延迟和预防这种损害。使用富勒烯抑制或干扰Aβ的聚集已被证明是治疗AD的有前途的策略。富勒烯的疏水性损害了它与活细胞的相互作用，导致毒性。因此，有必要对促进其水溶性的分子进行功能化。在这项研究中，我们评估了丙二酸二乙酯C ₆₀的结构和动力学性质。分子动力学模拟研究富勒烯加合物及其在水溶液中的相应钠盐。通过径向分布函数，氢键计数，密度分布和溶剂可及表面积，我们证明丙二酸钠富勒烯加合物具有更高的水合能力，而相应的丙二酸二乙酯加合物则表现出疏水趋势，形成自聚集体。此外，我们计算三元系统中，包括淀粉状蛋白β肽1-42（AβP的密度分布₄₂）单体，发现双- ，三- ，四- ，和C的pentaadducts ₆₀丙二酸二钠加成物与淀粉样蛋白分子相互作用，部分阻止其自身聚集。这些数据支持对先前报道的理解，该报道表明丙二酸富勒烯钠作为AβP聚集抑制剂的效率。此外，我们通过动态光散射在体外进行测量，发现富勒烯聚集与孵育时间无关。