FAUST: Foldamers As Unnatural Signal Transducers

FAUST：折叠器作为非自然信号传感器

• 批准号: 2291569
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2291569
• 关键词: FAUST; Foldamers; Unnatural; Signal; Transducers

Research questionsThe cell membrane not only defines a cell but also acts as a protective barrier, which means that cells must use specialised transmembrane proteins in their membranes to communicate with the world around them. G-protein-coupled receptors (GPCRs) are one such class of protein. GPCRs transmit a signal when an external messenger molecule (the 'signal') binds to their exterior, which induces conformational changes in the protein that then trigger the release of a message within the cell. The creation of completely artificial molecules that can copy GPCR behaviour and transmit messages across membranes (a distance of several nanometres) would lead to many exciting opportunities. For example, they could provide artificial signalling pathways that 'short-circuit' natural signalling networks, reprograming cells while providing fundamental scientific insights. Building on our recent work synthesising and studying compounds that mimic aspects of GPCR behaviour (published in Science and Nature Chemistry),1-4 we wish to initiate a new project at the interface of synthetic, supramolecular and biological chemistry; the "catch-and-release" of oxygen by membrane-spanning a-aminoisobutyric acid (Aib) foldamers in membranes.ApproachThis project will start with the chemical synthesis of Aib oligomers that can bind to haemoglobin. These folded oligomers ("foldamers") will be designed to bind a messenger molecule, which causes them to change shape. This shape change will be transmitted along the multi-nanometre length of the foldamer, to perturb haemoglobin conformation and thereby turn oxygen binding on or off. These foldamers will then be used for the "catch-and-release" of oxygen in 'artificial cells' (vesicles) that contain haemoglobin. Finally these foldamers would be inserted into erythrocyte membranes and messenger binding relayed into the cell interior, leading to changed oxygen binding by internal haemoglobin. This unique system would be the first synthetic signal transduction system applied to a natural cell, a huge advance towards truly synthetic biology.Novel physical sciences contentThe project will require the synthesis of large and complex folded molecules that will be embedded in phospholipid bilayers, where their properties will be studied, for example by microscopy and spectroscopy. There will also be the quantitative analysis of the effect of these molecules on the properties of haemoglobin. It will provide the student with extensive training in chemical synthetic methodology, analytical chemistry and supramolecular chemistry. The student will apply different types of physical sciences metrology to protobiological and synthetic biological constructs, leading to a deeper understanding of the natural signaling systems in a cell.References[1] R. A. Brown, V. Diemer, S. J. Webb, J. Clayden, Nature Chem. 2013, 5, 853. [2] M. De Poli, W. Zawodny, O. Quinonero, M. Lorch, S.J. Webb, J. Clayden, Science 2016, 352, 575. [3] F. G. A. Lister, B. A. F. Le Bailly, S. J. Webb, J. Clayden, Nature Chem. 2017, 9, 420.[4] Lister, F. G. A.; Eccles, N.; Pike, S. J.; Brown, R. A.; Whitehead, G. F. S.; Raftery, J.; Webb, S. J.; Clayden, J. Chem. Sci. 2018, 9, 6860.

研究质疑细胞膜不仅定义了细胞，而且还起到了保护性屏障的作用，这意味着细胞必须在其膜上使用专门的跨膜蛋白与周围的世界进行交流。 G蛋白偶联受体（GPCR）是一种这样的蛋白质。当外部信使分子（“信号”）与其外部结合时，GPCR会传递信号，这会诱导蛋白质中的构象变化，然后触发细胞内消息的释放。可以创建完全人工分子，这些分子可以复制GPCR行为并跨膜传输消息（几种纳米的距离）会带来许多令人兴奋的机会。例如，他们可以提供“短路”自然信号网络的人工信号通路，在提供基本的科学见解的同时重新编程。以我们最近的工作合成和研究模仿GPCR行为方面的化合物（发表在科学和自然化学中）的基础上，1-4我们希望在合成，超分子和生物学的界面上启动一个新项目；膜中跨膜a-氨基丁酸（AIB）折叠剂的氧气“捕获和释放”将从可以与血红蛋白结合的AIB寡聚物的化学合成开始。这些折叠的低聚物（“ Foldamers”）的设计旨在结合信使分子，从而使它们改变形状。这种形状变化将沿折叠剂的多纳米长度传输，以扰动血红蛋白构象，从而使氧结合在或关闭。然后，这些折叠剂将用于含有血红蛋白的'人造细胞'（囊泡）中的氧气“捕获和释放”。最后，这些折叠剂将被插入红细胞膜中，并将信使结合传递到细胞内部，从而导致内部血红蛋白的氧结合改变。这个独特的系统将是应用于天然细胞的第一个合成信号转导系统，这是实现真正合成生物学的巨大进步。主题物理科学内容该项目将需要合成大而复杂的折叠分子，这些分子将嵌入磷脂双层中，例如，在其中研究了它们的特性，例如，通过显微镜和光谱检查。还将对这些分子对血红蛋白特性的影响进行定量分析。它将为学生提供有关化学合成方法，分析化学和超分子化学的广泛培训。学生将将不同类型的物理科学计量学应用于原始生物学和合成生物学结构，从而更深入地了解细胞中的自然信号系统。 2013，5，853。[2] M. de Poli，W。Zawodny，O。Quinonero，M。Lorch，S.J。韦伯（J. 2017，9，420。[4] Lister，F。G. A。; Eccles，n。; Pike，S.J。;布朗，R。A。; Whitehead，G。F. S。； Raftery，J。； Webb，S.J。; Clayden，J。Chem。科学。 2018，9，6860。