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.

研究问题细胞膜不仅定义了细胞，还充当保护屏障，这意味着细胞必须使用膜中专门的跨膜蛋白来与周围的世界进行交流。 G 蛋白偶联受体 (GPCR) 就是这样一类蛋白质。当外部信使分子（“信号”）与其外部结合时，GPCR 会传输信号，从而诱导蛋白质构象变化，然后触发细胞内信息的释放。创建可以复制 GPCR 行为并跨膜（几纳米的距离）传输信息的完全人工分子将带来许多令人兴奋的机会。例如，它们可以提供人工信号通路，使自然信号网络“短路”，重新编程细胞，同时提供基本的科学见解。基于我们最近合成和研究模拟 GPCR 行为方面的化合物的工作（发表在《科学》和《自然化学》上）1-4，我们希望在合成、超分子和生物化学领域启动一个新项目；通过膜中的跨膜α-氨基异丁酸（Aib）折叠体“捕获并释放”氧气。方法该项目将从可与血红蛋白结合的Aib低聚物的化学合成开始。这些折叠的低聚物（“折叠体”）将被设计为结合信使分子，从而导致它们改变形状。这种形状变化将沿着折叠体的多纳米长度传递，以扰乱血红蛋白构象，从而打开或关闭氧结合。然后，这些折叠体将用于在含有血红蛋白的“人造细胞”（囊泡）中“捕获并释放”氧气。最后，这些折叠体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与氧的结合发生变化。这个独特的系统将是第一个应用于自然细胞的合成信号转导系统，这是真正合成生物学的巨大进步。新颖的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，其中它们的将通过例如显微镜和光谱学来研究特性。还将定量分析这些分子对血红蛋白特性的影响。它将为学生提供化学合成方法、分析化学和超分子化学方面的广泛培训。学生将把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结构，从而更深入地了解细胞中的自然信号系统。参考文献[1] R. A. Brown、V. Diemer、S. J. Webb、J. Clayden，《自然》化学。 2013, 5, 853。 [2] M. De Poli, W. Zawodny, O. Quinonero, M. Lorch, S.J. Webb, J. Clayden，科学 2016, 352, 575。 [3] F. G. A. Lister，B. A. F. Le Bailly，S. J. Webb，J. Clayden，自然化学。 2017年9月420日[4]李斯特，F.G.A.；埃克尔斯，N.；派克，S.J.；布朗，R.A.；怀特海德，G.F.S.；拉夫特里，J.；韦伯，S.J.；克莱登，J.化学。科学。 2018 年 9 月 6860。