Designer Chemistry to Probe Supramolecular Assembly Mechanism and Function

自组装允许构建大型复杂的3D功能结构，这些结构在健康和疾病方面都具有重要的生物学意义。这种结构形成的方式（即它们的组装机制或途径）还没有得到很好的理解;这是因为组装途径涉及多个结构的同时和动态形成，其中一些结构与最终的功能结构相关，一些结构与最终的功能结构无关，甚至其他结构本身具有功能。因此，一个根本性的挑战是实时监测这些组件，以便在结构水平上了解它们的组装途径，并告知我们干预这些过程的能力。对于生物功能组件来说，这一挑战更大，因为需要能够跟踪细胞中的单个组装中间体;这将使科学家能够监测它们的位置以及它们与细胞机器的其他组件相互作用以发挥其功能。 为了应对这一挑战，这项工作将开发一种方法，允许自组装途径中的单个物种被捕获并标记以进行进一步表征。使用专门的光化学将使我们能够拍摄组装系统的快照，并与能够分离和鉴定复杂混合物中的单个物种的质谱技术相结合，允许以残留物特定的细节和实时表征组装中间体。同时，我们将开发定制的合成化学，使个体/群体，组装中间体被进一步功能化，一旦他们被困，这将使我们开始研究这些中间体在细胞环境中的作用。 我们将把我们的方法应用于从A β肽中提取的淀粉样蛋白形成肽，A β肽形成淀粉样蛋白原纤维，在阿尔茨海默病的发展和进展中起着重要作用。因此，除了该项目将开发的基础和通用知识，工具和方法外，我们还将对具有巨大医学和社会意义的自组装途径产生新的理解。淀粉样蛋白β（Abeta）肽的细胞外斑块是阿尔茨海默病的标志，阿尔茨海默病是导致痴呆的几种神经退行性疾病之一。神经退化是一个主要的全球性问题;根据阿尔茨海默氏症研究，痴呆症影响约800，000人在英国意味着约2500万英国人口有一个亲密的朋友或家庭成员患有它。事实上，据估计，痴呆症花费英国经济每年230亿英镑，这比癌症和心脏病的总和还要多。然而，目前还不清楚如何最好地靶向条件，因为在分子水平上的Abeta功能的方式还不清楚。

Self-assembly permits the construction of large complex 3D functional structures that are biologically important both in health and disease. The manner in which such structures are formed (i.e. their mechanism or pathway of assembly) is not well-understood; this is because assembly pathways involve simultaneous and dynamic formation of multiple structures some of which are relevant to the final functional structure, some which are not and even others which are functional in their own right. Therefore, a fundamental challenge is to characterise such assemblies in real-time so as to understand their assembly pathways at a structural level and to inform our ability to intervene in these processes. This challenge is even greater for biologically functional assemblies arising from a need to be able to track individual assembly intermediates in cells; this would allow scientists to monitor their location and what other components of the cellular machinery they interact with to exert their function. To address this challenge, this work will develop an approach to allow individual species in a self-assembly pathway to be trapped and tagged for further characterisation. Using specialised photochemistry will allow us to take a snapshot of an assembling system and, in combination with a mass spectrometry technique able to separate and characterise individual species within a complex mixture, allow characterisation of assembly intermediates in residue-specific detail and real-time. In tandem, we will develop tailored synthetic chemistry to allow individual/ populations of, assembly intermediates to be further functionalised once they have been trapped and this will allow us to begin to study the role of these intermediates in a cellular environment. We will apply our approach to an amyloid-forming peptide from the Abeta peptide which forms amyloid fibrils and plays a central role in the development and progression of Alzheimer's disease. Thus, in addition to the fundamental and generic knowledge, tools and methods that the project will develop, we will generate new understanding on a self-assembly pathway of huge medical and societal significance. Extracellular plaques of the amyloid-beta (Abeta) peptide are a signature of Alzheimer's disease, one of several neurodegenerative conditions that result in dementia. Neurodegeneration is a major global problem; according to Alzheimer's Research, dementia affects ~ 800,000 people in the UK meaning some 25 million of the UK population have a close friend or family member who suffers from it. Indeed, it has been estimated that dementia costs the UK economy £23 billion a year which is more than cancer and heart disease combined. However, it is unclear at this stage how to best target the condition because the way in which Abeta functions at a molecular level is not understood.