Artificial Transmembrane Molecular Machines Project Proposal

离子在细胞膜上的转运是所有活细胞的基本过程。这种转运的控制允许细胞通讯中的信号转导，pH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，这是通过离子通道实现的，离子通道本质上是跨越细胞膜的毛孔和蛋白质泵。由于突变导致的这些转运系统的错误调节可引起疾病，包括癫痫，这可能是由钠离子通道故障引起的，或囊性纤维化，其中氯离子的转运受损。能够介导跨膜离子运输的合成系统有可能在治疗环境中解决这些问题。这些可以包括人工离子通道，移动离子载体，或者最近的分子机器。后者是分子或多分子的集合，它们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，离子运输通常受到外部刺激的调节，例如信号传递过程中细胞膜电压的变化，pH值的变化，小分子与离子转运蛋白上受体的结合，或光。例如，视紫红质蛋白是视网膜中视杆细胞的一部分，在光线照射下改变其构象。这导致细胞膜上阳离子（带正电荷的离子）通道的关闭，最终改变了昏暗视觉的信号转导过程。离子接力转运体最近被认为是一种有效的途径来介导和控制离子在脂质双分子层膜上的转运。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页的另一个接力臂上，该接力臂将阴离子运送到膜的另一侧。该系统的光控制可以通过光异构反应来调节接力臂的长度，就像一个跨膜运输系统的分子机器。该项目的目标是开发新型离子继电器和跨膜分子机器，其中阳离子和阴离子传输可以通过各种生物相关刺激（如光和氧化还原刺激）进行调节。这些新分子机器的设计将以计算模型为指导，以进一步了解脂质双分子层内接力转运体的行为。该项目属于EPSRC“物理科学”研究领域，涉及“合成超分子化学”和“合成配位化学”的主题。

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".