Artificial Transmembrane Molecular Machines Project Proposal

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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".