Designer Chemistry to Probe Supramolecular Assembly Mechanism and Function

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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.