Department of Chemistry and Biochemistry, Missouri State University, 901 S. National Avenue, Springfield, Missouri 65897, United States.
Molecular Graphics and Modeling Laboratory, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66018, United States.
ACS Chem Neurosci. 2024 Jun 5;15(11):2359-2371. doi: 10.1021/acschemneuro.4c00226. Epub 2024 May 10.
Elucidating the underlying principles of amyloid protein self-assembly at nanobio interfaces is extremely challenging due to the diversity in physicochemical properties of nanomaterials and their physical interactions with biological systems. It is, therefore, important to develop nanoscale materials with dynamic features and heterogeneities. In this work, through engineering of hierarchical polyethylene glycol (PEG) structures on gold nanoparticle (GNP) surfaces, tailored nanomaterials with different surface properties and conformations (GNPs-PEG) are created for modulating the self-assembly of a widely studied protein, insulin, under amyloidogenic conditions. Important biophysical studies including thioflavin T (ThT) binding, circular dichroism (CD), surface plasmon resonance (SPR), and atomic force microscopy (AFM) showed that higher-molecular weight GNPs-PEG triggered the formation of amyloid fibrils by promoting adsorption of proteins at nanoparticle surfaces and favoring primary nucleation rate. Moreover, the modulation of fibrillation kinetics reduces the overall toxicity of insulin oligomers and fibrils. In addition, the interaction between the PEG polymer and amyloidogenic insulin examined using MD simulations revealed major changes in the secondary structural elements of the B chain of insulin. The experimental findings provide molecular-level descriptions of how the PEGylated nanoparticle surface modulates protein adsorption and drives the self-assembly of insulin. This facile approach provides a new avenue for systematically altering the binding affinities on nanoscale surfaces by tailoring their topologies for examining adsorption-induced fibrillogenesis phenomena of amyloid proteins. Together, this study suggests the role of nanobio interfaces during surface-induced heterogeneous nucleation as a primary target for designing therapeutic interventions for amyloid-related neurodegenerative disorders.
阐明纳米生物界面中淀粉样蛋白自组装的基本原理极具挑战性，这是因为纳米材料的物理化学性质多样化，以及它们与生物系统的物理相互作用。因此，开发具有动态特征和异质性的纳米级材料非常重要。在这项工作中，通过在金纳米粒子（GNP）表面工程化分级聚乙二醇（PEG）结构，制备了具有不同表面性质和构象的定制纳米材料（GNPs-PEG），用于调节广泛研究的蛋白质胰岛素在淀粉样条件下的自组装。包括硫黄素 T（ThT）结合、圆二色性（CD）、表面等离子体共振（SPR）和原子力显微镜（AFM）在内的重要生物物理研究表明，高分子量 GNPs-PEG 通过促进蛋白质在纳米粒子表面的吸附并有利于初级成核速率，触发了淀粉样纤维的形成。此外，纤化动力学的调节降低了胰岛素寡聚物和纤维的整体毒性。此外，使用 MD 模拟研究了 PEG 聚合物与淀粉样胰岛素之间的相互作用，发现胰岛素 B 链的二级结构元件发生了重大变化。实验结果提供了分子水平的描述，说明 PEG 化纳米粒子表面如何调节蛋白质吸附并驱动胰岛素的自组装。这种简便的方法通过调整其拓扑结构提供了一种系统改变纳米级表面结合亲和力的新途径，用于研究淀粉样蛋白吸附诱导的纤维形成现象。总之，这项研究表明纳米生物界面在表面诱导的多相成核过程中的作用，为设计与淀粉样蛋白相关的神经退行性疾病的治疗干预提供了一个主要目标。
