Artificial Transmembrane Molecular Machines Project Proposal

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".

The primary impact of the OxICFM CDT will be the highly-trained world-class scientists that it delivers. This impact will encompass both the short term (during their doctoral studies), the medium term (subsequent employment) and ultimately the longer timescale defined by their future careers and consequent impact on science, engineering and policy in the UK.

The impact of OxICFM students during their doctoral studies will be measured by the culture change in graduate training that the Centre brings about - in working at the interface between inorganic synthesis and manufacturing, and fostering cross-sector industry/academia working practices. By embedding not only from larger companies, but also SMEs, we have developed a training regime that has broader relevance across the sector, and the potential for building bridges by fostering new collaborations spanning enormous diversity in scientific focus and scale. Moreover, at a broader level, OxICFM offers to play a unique role as a major focus (and advocate) for manufacturing engagement with academic inorganic synthetic science in the UK.

From a scientific perspective, OxICFM will be uniquely able to offer a broad training programme incorporating innovative and challenging collaborative projects spanning all aspects of fundamental and applied inorganic synthesis, both molecular and materials based (40+ faculty). These will address key challenges in areas such as energy provision/storage, catalysis, and resource provision/renewal necessary to enhance the capability and durability of UK plc in the medium term. To give some idea of perspective, the output from previous CDTs in Oxford's MPLS Division include two start-up companies and in excess of 30 patents.

It is not only in the industrial and scientific realms that students will have impact during their timeframe of their doctorate. Part of the training programme will be in public engagement: team-based challenges in resource development/training and outreach exercises/implementation will form part of the annual summer school. These in turn will constitute a key part of the impact derived from the CDT by its engagement with the public - both face-to-face and through electronic/web-based media. As the centre matures, our aspiration is that our students - from diverse backgrounds - will act as ambassadors for the programme and promote even higher levels of inclusion from all parts of society.

For our partners, and businesses both large and small in the manufacturing sector, it will be our students who are considered the ultimate output of the OxICFM CDT. Our programme has been shaped by the need of such companies (frequently expressed in preliminary discussions) to recruit doctoral graduates who can apply themselves to a broad spectrum of multi-disciplinary challenges in manufacturing-related synthesis. OxICFM's cohort-based training programme integrates significant industry-led training components and has been designed to deliver a much broader skill set than standard PhD schemes. The current lack of CDT training at the interface of inorganic chemistry and manufacturing (and the relevance of inorganic molecules/materials to numerous industrial sectors) heightens the need for - and the potential impact of - the OxICFM CDT. Our students will represent a tangible and valuable asset to meet the long-term skills demand for scientists to develop new materials and nanotechnology identified in the UK Government's 2013 Foresight report.

In the longer term, the broad and relevant training delivered by OxICFM, and the uniquely wide perspective of the manufacturing sector it will deliver, will allow our graduates to obtain (and thrive in) positions of significant responsibility in industry and in research facilities/institutes. Ultimately we believe that many will go on to be future research leaders, driving innovation and changing research culture, and thereby making a lasting contribution to the UK economy.