FAUST: Foldamers As Unnatural Signal Transducers

研究问题细胞膜不仅定义了细胞，而且还起到了保护屏障的作用，这意味着细胞必须在其细胞膜中使用特殊的跨膜蛋白来与周围的世界沟通。G蛋白偶联受体(GPCRs)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，GPCRs传递一个信号，这会导致蛋白质的构象变化，然后触发细胞内的信息释放。能够复制gpr行为并通过膜传输信息(距离几纳米)的完全人造分子的创造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”，在提供基本的科学见解的同时，对细胞进行重新编程。在我们最近合成和研究模拟GPCR行为的化合物的工作(发表在《科学》和《自然化学》上)的基础上，1-4我们希望在合成、超分子和生物化学的界面上发起一个新的项目：通过膜跨a-氨基异丁酸(AIB)膜上的折叠体“捕捉并释放”氧。这些折叠的低聚物(“折叠体”)将被设计成结合信使分子，从而使它们改变形状。这种形状的改变将沿着折叠分子的多纳米长度传递，从而扰乱血红蛋白的构象，从而打开或关闭氧结合。然后，这些滤泡剂将被用来在含有血红蛋白的“人造细胞”(囊泡)中“捕捉和释放”氧气。最后，这些折叠分子被插入红细胞膜，信使结合传递到细胞内部，导致内部血红蛋白的氧结合发生变化。这一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，这是向真正的合成生物学迈进的一大步。新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，在那里将通过显微镜和光谱分析来研究它们的性质。还将对这些分子对血红蛋白性质的影响进行定量分析。它将为学生提供广泛的化学合成方法学、分析化学和超分子化学方面的培训。学生将应用不同类型的物理科学计量学到原生生物和合成生物结构，从而加深对细胞中自然信号系统的理解。参考文献[1]R.A.Brown，V.Diemer，S.J.Webb，J.Clayden，Natural Chem。2013年，5853人。[2]M.de Poli，W.Zawodny，O.Quinonero，M.Lorch，S.J.Webb，J.Clayden，Science 2016,352,575。[3]首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容2017年，9,420.[4]李斯特，F.G.A.；埃克尔斯，N.；派克，S.J.；布朗，R.A.；怀特黑德，G.F.S.；雷弗里，J.；韦伯，S.J.；克莱登，J.化学。SCI。2018年，9,6860。

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.