碳纳米材料与蛋白质构象疾病中关键蛋白的相互作用及分子机理研究

The ever increasing protein conformational diseases (PCD) such as Alzheimer’s disease (AD) has caused a significant challenge to human health worldwide (AD alone is the No. 4 cause of death), with no immediate cure in sight – the limited number of current small-molecule-based drugs can only reduce some of the symptoms, but not stop the disease progression. Meanwhile, the emerging nanotechnology and nanomaterial is providing a new direction for the development of anti-PCD therapies. In this project, we will utilize both experimental and theoretical approaches to study the interaction of graphene-based carbon nanomaterials with key protein aggregates, including the molecular mechanism and dynamical process, thus to reveal the fundamental physics and chemistry to help select the potential candidate nanomaterials. We will first characterize the physicochemical properties of these graphene-based nanomaterials. Then, we will use both in vitro and in vivo experiments to examine their detailed interactions with amyloid peptides, potential efficacy against PCD (AD in particular), and their biocompatibility. Meanwhile, we will use both molecular dynamics simulations and quantum mechanics calculations to study the impact of structural properties and surface modifications of these nanomaterials on their capability in inhibiting peptide aggregation, breaking/removing mature amyloid fibrils, and underlying molecular mechanism. We will also simulate the interaction dynamics of these nanomaterials with the cell membrane and other important biological macromolecules. With a combined in vivo, in vitro and in silico approach, this project aims to reveal the molecular driving forces of these graphene-based carbon nanomaterials in their interaction with amyloid peptides, the fundamental rules governing their biological functions, and any potential bio-effects. The successful completion of this project will promote the development of novel nanomedicine for protein conformational diseases.

蛋白质构象疾病如老年痴呆症已成为人类第四大致死病因，目前有限的基于传统小分子的药物只能改善其某些症状却无法从根本上阻止病情的恶化。当前纳米材料在生物医学领域的飞速发展有望为预防及治疗该类疾病提供新的思路。本项目通过理论与实验的结合，系统研究石墨烯等碳纳米材料与该类疾病的关键蛋白质的相互作用，内在分子机制，以及软凝聚态动力学过程，从而揭示具有普遍性的物理化学规律来协助筛选具潜在疗效的碳纳米材料，并进一步探讨其生物学效应。我们首先研究相关纳米材料的理化性质，然后通过分子、细胞和动物实验研究其与各级肽链积聚体的作用方式，潜在疗效，以及生物效应。同时运用分子动力学模拟与量化计算建立理论模型，结合实验探索材料物化参数及修饰对其抑制肽链积聚、破坏清除成熟纤维、降低细胞生物毒性等功效的影响，重点阐述其与各级积聚体以及细胞膜的相互作用及其分子机制。本项目对开发抗蛋白质构象疾病的纳米药物具有积极指导意义。

在本项目中我们通过将理论模拟与实验科学有机结合，研究了系列碳纳米材料和有机小分子化合物（包括：石墨烯，C2N，C3N，C3N4，f-Gd@C82，聚合碳纳米点，羊毛甾醇和DHA等）与蛋白质构象疾病（主要包括：阿尔兹海默症（AD），II-型糖尿病，亨廷顿舞蹈症，和白内障）中重要蛋白或肽链的相互作用，内在分子机理，及其软凝聚态动力学过程。我们还从细胞层面探讨了相关纳米材料的生物学效应，包括：抑制肽链聚集对肽链聚集细胞毒性的缓解作用，以及材料本身的细胞相容性。我们还通过综合比较各种材料的本身的物理化学性质和生物利用度等，具体包括：制备的难易程度，品质的可控性，分散性，生物相容性，粒径大小，血脑屏障通透能力评估等，筛选出了CN纳米点可能具有更好的AD治疗效果。随后，我们从动物层面研究了C3N纳米点对于小鼠AD症状的治疗作用，发现其能显著增强AD小鼠的空间认知和新物学习能力。这些结果预示着C3N纳米点具有缓解或治疗AD作用。尽管，真正要将这些材料应用于AD的治疗还需要系统的毒理学行为评估，药理药代的研究等。我们的研究仍然揭示了一些具有普遍性的物理化学规律来协助筛选具有潜在疗效的碳纳米材料，也为设计基于碳基纳米点的AD治疗药物奠定了非常重要的科学基础。