State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, No.122 Luoshi Road, Wuhan 430070, China.
School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, No.122 Luoshi Road, Wuhan 430070, China.
ACS Appl Mater Interfaces. 2021 Feb 3;13(4):4894-4904. doi: 10.1021/acsami.0c21906. Epub 2021 Jan 24.
Chemical and physical properties of nanobio interface substantially affect the conformational transitions of adjacent biomolecules. Previous studies have reported the chiral effect and charge effect of nanobio interface on the misfolding, aggregation, and fibrillation of amyloid protein. However, the isomeric effect of nanobio interface on protein/peptides amyloidosis is still unclear. Here, three isomeric nanobio interfaces were designed and fabricated based on the same sized gold nanoclusters (AuNCs) modified with 4-mercaptobenzoic acid (-MBA), 3-mercaptobenzoic acid (-MBA), and 2-mercaptobenzoic acid (-MBA). Then three isomeric AuNCs were employed as models to explore the isomeric effect on the misfolding, aggregation, and fibrillation of Aβ at nanobio interfaces. Site-specific replacement experiments on the basis of theoretical analysis revealed the possible mechanism of Aβ interacting with isomeric ligands of AuNCs at the nanobio interfaces. The distance and orientation of -COOH group from the surface of AuNCs can affect the electrostatic interaction between isomeric ligands and the positively charged residues (R5, K16, and K28) of Aβ, which may affect the inhibition efficiency of isomeric AuNCs on protein amyloidosis. Actually, the amyloid fibrillation kinetics results together with atomic force microscope (AFM) images, dynamic light scattering (DLS) results and circular dichroism (CD) spectra indeed proved that all the three isomeric AuNCs could inhibit the misfolding, aggregation and fibrillation of Aβ in a dose-dependent manner, and the inhibition efficiency was definitely different from each other. The inhibition efficiency of -MBA-AuNCs was higher than that of -MBA-AuNCs and -MBA-AuNCs at the same dosage. These results provide an insight for isomeric effect at nanobio interfaces, and open an avenue for structure-based nanodrug design target Alzheimer's disease (AD) and even other protein conformational diseases.
纳米生物界面的化学和物理性质极大地影响了相邻生物分子的构象转变。先前的研究报告了纳米生物界面对错误折叠、聚集和纤维形成的淀粉样蛋白的手性效应和电荷效应。然而，纳米生物界面对蛋白质/肽淀粉样变性的异构效应仍不清楚。在这里，基于相同尺寸的巯基苯甲酸（-MBA）、3-巯基苯甲酸（-MBA）和 2-巯基苯甲酸（-MBA）修饰的金纳米簇（AuNCs）设计并制备了三种异构纳米生物界面。然后，以三种异构 AuNCs 为模型，研究了在纳米生物界面上异构效应对 Aβ错误折叠、聚集和纤维形成的影响。基于理论分析的定点取代实验揭示了 Aβ与 AuNCs 异构配体在纳米生物界面相互作用的可能机制。-COOH 基团与 AuNCs 表面的距离和方向会影响异构配体与 Aβ的正电荷残基（R5、K16 和 K28）之间的静电相互作用，这可能会影响异构 AuNCs 对蛋白质淀粉样变性的抑制效率。实际上，淀粉样纤维形成动力学结果结合原子力显微镜（AFM）图像、动态光散射（DLS）结果和圆二色性（CD）光谱确实证明，所有三种异构 AuNCs 都可以以剂量依赖的方式抑制 Aβ的错误折叠、聚集和纤维形成，并且抑制效率彼此之间肯定不同。在相同剂量下，-MBA-AuNCs 的抑制效率高于-MBA-AuNCs 和-MBA-AuNCs。这些结果为纳米生物界面的异构效应提供了深入的了解，并为基于结构的纳米药物设计针对阿尔茨海默病（AD）甚至其他蛋白质构象疾病的目标开辟了一条途径。
