Deng Yuzhou, Gao Guanbin, Yu Liangchong, Zhang Zijun, Zhang Bin, Li Hu, Zhang Xinyu, Shen Lei, Sun Taolei
State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, 122 Luoshi Road, Wuhan, 430070, P. R. China.
Hubei Key Laboratory of Nanomedicine for Neurodegenerative Diseases, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 122 Luoshi Road, Wuhan, 430070, P. R. China.
Small. 2024 Oct;20(40):e2312046. doi: 10.1002/smll.202312046. Epub 2024 Jun 3.
Accurate construction of artificial nano-chaperones' structure is crucial for precise regulation of protein conformational transformation, facilitating effective treatment of proteopathy. However, how the ligand-anchors of nano-chaperones affect the spatial conformational changes in proteins remains unclear, limiting the development of efficient nano-chaperones. In this study, three types of gold nanoparticles (AuNPs) with different core/ligands interface anchor structures (Au─NH─R, Au─S─R, and Au─C≡C─R, R = benzoic acid) are synthesized as an ideal model to investigate the effect of interfacial anchors on Aβ and amylin fibrillization. Computational results revealed that the distinct interfacial anchors imparted diverse distributions of electrostatic potential on the nanointerface and core/ligands bond strength of AuNPs, leading to differential interactions with amyloid peptides. Experimental results demonstrated that all three types of AuNPs exhibit site-specific inhibitory effects on Aβ fibrillization due to preferential binding. For amylin, amino-anchored AuNPs demonstrate strong adsorption to multiple sites on amylin and effectively inhibit fibrillization. Conversely, thiol- and alkyne-anchored AuNPs adsorb at the head region of amylin, promoting folding and fibrillization. This study not only provided molecular insights into how core/ligands interfacial anchors of nanomaterials induce spatial conformational changes in amyloid peptides but also offered guidance for precisely engineering artificial-chaperones' nanointerfaces to regulate the conformational transformation of proteins.
精确构建人工纳米伴侣的结构对于精确调控蛋白质构象转变、促进蛋白病的有效治疗至关重要。然而，纳米伴侣的配体锚如何影响蛋白质的空间构象变化仍不清楚，这限制了高效纳米伴侣的开发。在本研究中，合成了三种具有不同核/配体界面锚结构（Au─NH─R、Au─S─R和Au─C≡C─R，R = 苯甲酸）的金纳米颗粒（AuNP），作为研究界面锚对Aβ和胰岛淀粉样多肽纤维化影响的理想模型。计算结果表明，不同的界面锚在纳米界面上赋予了不同的静电势分布以及AuNP的核/配体键强度，导致与淀粉样肽的相互作用不同。实验结果表明，由于优先结合，所有三种类型的AuNP对Aβ纤维化均表现出位点特异性抑制作用。对于胰岛淀粉样多肽，氨基锚定的AuNP对胰岛淀粉样多肽的多个位点表现出强吸附作用，并有效抑制纤维化。相反，硫醇和炔烃锚定的AuNP吸附在胰岛淀粉样多肽的头部区域，促进折叠和纤维化。这项研究不仅提供了关于纳米材料的核/配体界面锚如何诱导淀粉样肽空间构象变化的分子见解，还为精确设计人工伴侣的纳米界面以调控蛋白质的构象转变提供了指导。
