Artificial Transmembrane Molecular Machines Project Proposal

人工跨膜分子机器项目提案

• 批准号: 2714587
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2714587
• 关键词: Artificial; Transmembrane; Molecular; Machines; Project

The transport of ions across the cell membrane is an essential process in all living cells. Control of this transport allows for signal transduction in cellular communication, regulation of the pH, neuron firing and maintaining cellular homeostasis, amongst numerous other functions. In nature, this is achieved by ion channels, which are essentially pores spanning the cell membrane, and protein pumps. Mis- regulation of these transport systems due to mutations can cause diseases, including epilepsy which may be caused by the malfunctioning of sodium ion channels, or cystic fibrosis, where the transport of chloride ions is impaired. Synthetic systems capable of mediating transmembrane ion transport have the potential to address these issues in a therapeutic context. These can include artificial ion channels, mobile ion carriers or, more recently, molecular machines. The latter are molecules, or assemblies of multiple molecules, that exploit a nano-mechanical motion at the molecular level to carry out a task, such as moving ions from A to B.In nature, the ion transport is often regulated by external stimuli, such as a change in voltage across the cell membrane during signal transmission, a change in pH, small molecule binding to a receptor on the ion transporter protein, or light. For example, the protein rhodopsin is part of the rod cells in the retina and changes its conformation upon light irradiation. This leads to the closing of cation (positively charged ion) channels in the cell membrane, which ultimately changes the signal transduction process involved in dim light vision.Ion relay transporters have recently emerged as an effective way to mediate, and control, ion transport across lipid bilayer membranes. These feature a movable arm that can bind anions (negatively charged ions) and can reach halfway into the membrane. Here the anion is transferred onto the arm of another relay sitting in the other leaflet of the membrane, which transports the anion to the other side of the membrane. Photo-control of this system can be engineered by using photo-isomerisation reactions to modulate the length of the relay arm, acting as a molecular-machine like transmembrane transport system.The aim of this project will be to develop new classes of ion relays and transmembrane molecular machines, in which both cation and anion transport can be modulated through a diverse range of biologically relevant stimuli, such as light and redox stimuli. The design of these new molecular machines will be guided by computational modelling to obtain further insight into behaviour of the relay transporter inside the lipid bilayer.This project falls within the EPSRC "physical sciences" research area, and relates to the themes "synthetic supramolecular chemistry" and "synthetic coordination chemistry".

离子穿过细胞膜的运输是所有活细胞中的基本过程。对这种转运的控制允许细胞通讯中的信号转导、pH的调节、神经元放电和维持细胞稳态，以及许多其他功能。在自然界中，这是通过离子通道和蛋白泵实现的，离子通道基本上是跨越细胞膜的孔。由于突变引起的这些转运系统的失调可引起疾病，包括可能由钠离子通道故障引起的癫痫，或其中氯离子转运受损的囊性纤维化。能够介导跨膜离子转运的合成系统具有在治疗背景下解决这些问题的潜力。这些可以包括人工离子通道、移动的离子载体或最近的分子机器。后者是分子或多个分子的组装体，其利用分子水平的纳米机械运动来执行任务，例如将离子从A移动到B。在自然界中，离子转运通常由外部刺激调节，例如信号传输期间细胞膜上的电压变化、pH变化、与离子转运蛋白上的受体结合的小分子或光。例如，蛋白质视紫红质是视网膜中视杆细胞的一部分，并且在光照射时改变其构象。这导致细胞膜上阳离子通道的关闭，最终改变了微光视觉中的信号转导过程。离子中继转运蛋白是近年来发现的一种有效的介导和控制离子跨脂质双层膜转运的途径。它们具有一个可移动的臂，可以结合阴离子（带负电荷的离子），并可以到达膜的一半。在这里，阴离子被转移到位于膜的另一个小叶中的另一个中继器的臂上，该中继器将阴离子输送到膜的另一侧。该系统的光控制可以通过使用光异构化反应来调节中继臂的长度，作为一个类似跨膜转运系统的分子机器，本项目的目的是开发新的离子中继和跨膜分子机器，其中阳离子和阴离子的转运可以通过各种生物相关的刺激来调节，例如光和氧化还原刺激。这些新的分子机器的设计将通过计算模型来指导，以获得对脂质双层内的中继转运体的行为的进一步了解。该项目福尔斯属于EPSRC“物理科学”研究领域，并涉及“合成超分子化学”和“合成配位化学”的主题。