淀粉质β多肽（Aβ）的聚集和纤维化是阿尔茨海默症形成的重要过程。本项目旨在建立新型Aβ聚集抑制的设计方法并研究其作用机理。首先研究Aβ与其多肽抑制剂ZAβ3的亲和结合作用，发现ZAβ3分子中的关键氨基酸残基和分布规律，构建Aβ的亲和结合分子模型和仿生短肽配基库，进而建立多级分子模拟筛选方法，获得备选短肽配基；然后利用热力学实验分析，鉴定和发现高选择性短肽配基，构筑生物相容性亲和纳米粒子；研究亲和纳米粒子与Aβ作用的热力学特性和抑制Aβ聚集的动力学规律，优化设计亲和纳米抑制剂；进行细胞毒性实验和抗体斑点印迹实验，研究纳米抑制剂对Aβ聚集的解毒作用和Aβ结合特性；最后开展Aβ与亲和纳米抑制剂表面作用的分子模拟研究。通过系统的动力学、热力学和生物学实验研究以及分子模拟分析，建立亲和纳米抑制剂作用的机理模型。本项目成果可为新型纳米抑制剂的设计和开发奠定科学和技术基础，具有重要理论意义和实际价值。

The aggregation and fibrillation of amyloid β-peptide (Aβ) are the main cause of Alzheimer's disease. This project is proposed to develop novel inhibitors for the aggregation and fibrillation of Aβ and to study the working mechanisms of the inhibitors. First of all, molecular interactions in the affinity complex of Aβ-ZAβ3 will be investigated by molecular dynamics (MD) simulations to find the key amino acid residues (hot spots) in ZAβ3 and their distribution. Based on the distribution of the hot spots, an affinity molecular model will be constructed, leading to the formation of a biomimetic short peptide library. Then, a multi-stage MD simulation strategy is established to efficiently screen the peptides and determine the high-ranking peptide ligands for further experimental identification. From the high-ranking peptides determined by MD simulations, experiments of binding thermodynamics will be carried out to determine a few high-affinity peptide ligands. The affinity ligands are coupled to biocompatible nanoparticles to construct affinity nanoparticles. By investigating the thermodynamic interactions between the affinity nanoparticles and Aβ as well as the inhibition kinetics on Aβ aggregation, the affinity nano-inhibitors can be optimized. Then cell toxicity assay and dot blot assay will be performed to study the detoxication effects of the nano-inhibitors and their binding characteristics with Aβ. Finally, MD simulations of the interactions between Aβ and the nano-inhibitor surface will be conducted to elucidate the molecular details involved in the inhibition. Based on the comprehensive kinetics, thermodynamics, biological assays and MD simulations, a mechanistic model for the inhibition effects of the nano-inhibitors on Aβ aggregation can be proposed. Therefore, this project is of importance because the outcomes of this project will form the scientific and technological bases for the further design and development of Aβ aggregation inhibitors.