中文摘要：

淀粉样多肽（amyloid-Bpeptide，Ap）聚集是引起阿尔兹海默症（Alzheimer’s disease，AD）的主要原因。开发Aβ聚集抑制剂是治疗AD的最有效手段之一。利用噬菌体展示技术筛选出来的ZAB3蛋白质能够有效抑制Aβ聚集，但ZAβ3和Aβ之间的作用区域和关键氨基酸残基尚不清楚。针对此问题，本研究利用分子动力学模拟、MM-PBSA自由能计算和分解方法研究了ZAβ3-Aβ16-40复合物之间的相互作用机制。结果表明，ZAβ3的β-股和Aβ16-40之间的亲和作用占主导，而ZAβ3的a-螺旋贡献很小。利用分子力学．帕松波尔茨曼溶剂可及化表面积方法（MM-PBSA）自由能分解发现zAB3的热点残基为E15、116、v17、Y18、L19、P20、N21和L22，而Aβ16-40的热点残基为F19、F20、A21、E22、D23、K28、131、132、G33、L34、M35、V36、G38和V40、ZAB3通过将发夹型AB单体包埋在a-螺旋围成的疏水性腔体内来阻碍Aβ聚集。这种结合模式为设计高效的Aβ蛋白质类抑制剂提供了三个基本要素：高亲和性的结合片段（β-股）、附属结构（a-螺旋）和通过二硫键形成的稳定构象。高亲和性结合片段能竞争性地与Aβ单体结合，附属结构a-螺旋可以阻碍其它Aβ单体靠近，而稳定的构象是上述两种要素发挥作用的基础，三者协同作用可以有效地抑制Aβ聚集。

英文摘要：

Alzheimer＇s disease （AD） is mainly caused by the aggregation of amyloid-β （Aβ） protein. Development of inhibitors to prevent Aβ aggregation is the most efficient method to devise a cure for AD. Aβ aggregation has been found to be inhibited by the affibody protein ZAI]3, selected via phage display. However, the molecular basis of affinity interactions between Aβ and ZAβ3, the interaction region, and important residues of Aβ and ZAβ3 remain unclear. Herein, molecular dynamics simulations and free energy calculation and decomposition using the molecular mechanics-Poisson-Boltzmann surface area method （MM-PBSA） were coupled to investigate the molecular mechanism underlying interactions between Aβ and ZAβ3. Interactions between the β-strand of ZAβ3 and Aβ16-40 were found to contribute greatly to their binding free energy, while that between the a-helix of ZAβ3 and ZAβ3 has a smaller contribution. Based on the free energy decomposition, hotspot residues of ZAβ3 are E15, 116, V17, Y18, L19, P20, N21, and L22 and those of Aβ16-40 include F19, F20, A21, E22, D23, K28, β1, β2, G33, L34, M35, V36, G38, and V40. ZAβ3 stabilizes the β-sheet by burying the two mostly nonpolar faces of the Aβ hairpin within a large hydrophobic tunnel-like cavity formed by the β-helix. The identified binding motif can be used as a starting point for rational design of protein inhibitors with high affinity for Aβ to prevent Aβ aggregation. The three key characteristics of efficient protein inhibitors are the presence of a high-affinity site （β-strand）, a large accessory structure （a-helix）, and a stable conformation owing to disulfide bonds. The high-affinity site can competitively bind to the Aβ monomer, and the large accessory structure can block other Aβ monomers; both these elements require a stable conformation via disulfide bonds. These three characteristics of a protein inhibitor can be employed together to suppress Aβ aggregation. Key Words： Protein inhibitor; Amyloid-β protein; Molecu