Reducing carbon emissions and securing energy supplies are crucial international goals to which energy demand reduction must make a major contribution. On a national level, demand reduction, deployment of new and renewable energy technologies, and decarbonisation of the energy supply are essential if the UK is to meet its legally binding carbon reduction targets. As a result, this area is an important theme within the EPSRC's strategic plan, but one that suffers from historical underinvestment and a serious shortage of appropriately skilled researchers. Major energy demand reductions are required within the working lifetime of Doctoral Training Centre (DTC) graduates, i.e. by 2050. Students will thus have to be capable of identifying and undertaking research that will have an impact within their 35 year post-doctoral career. The challenges will be exacerbated as our population ages, as climate change advances and as fuel prices rise: successful demand reduction requires both detailed technical knowledge and multi-disciplinary skills. The DTC will therefore span the interfaces between traditional disciplines to develop a training programme that teaches the context and process-bound problems of technology deployment, along with the communication and leadership skills needed to initiate real change within the tight time scale required. It will be jointly operated by University College London (UCL) and Loughborough University (LU); two world-class centres of energy research. Through the cross-faculty Energy Institute at UCL and Sustainability Research School at LU, over 80 academics have been identified who are able and willing to supervise DTC students. These experts span the full range of necessary disciplines from science and engineering to ergonomics and design, psychology and sociology through to economics and politics. The reputation of the universities will enable them to attract the very best students to this research area.The DTC will begin with a 1 year joint MRes programme followed by a 3 year PhD programme including a placement abroad and the opportunity for each DTC student to employ an undergraduate intern to assist them. Students will be trained in communication methods and alternative forms of public engagement. They will thus understand the energy challenges faced by the UK, appreciate the international energy landscape, develop people-management and communication skills, and so acquire the competence to make a tangible impact. An annual colloquium will be the focal point of the DTC year acting as a show-case and major mechanism for connection to the wider stakeholder community.The DTC will be led by internationally eminent academics (Prof Robert Lowe, Director, and Prof Kevin J Lomas, Deputy Director), together they have over 50 years of experience in this sector. They will be supported by a management structure headed by an Advisory Board chaired by Pascal Terrien, Director of the European Centre and Laboratories for Energy Efficiency Research and responsible for the Demand Reduction programme of the UK Energy Technology Institute. This will help secure the international, industrial and UK research linkages of the DTC.Students will receive a stipend that is competitive with other DTCs in the energy arena and, for work in certain areas, further enhancement from industrial sponsors. They will have a personal annual research allowance, an excellent research environment and access to resources. Both Universities are committed to energy research at the highest level, and each has invested over 3.2M in academic appointments, infrastructure development and other support, specifically to the energy demand reduction area. Each university will match the EPSRC funded studentships one-for-one, with funding from other sources. This DTC will therefore train at least 100 students over its 8 year life.

The aim of this project is to develop a new computational tool for modelling large scale conformational change in biomolecules. The tool will be used to characterise the molecular mechanism of kinase (in)activation. In collaboration with Johnson & Johnson, the in silico model will be tested at bench level for further insight and model refinement. The proposed tool will build on recent software developments in the computational biophysics group of Dr Bryce. At the interface of computer science and biophysics, we have implemented a method[1] which combines the power of swarm intelligence methods with molecular dynamics simulation to significantly accelerate conformational searching. Applying this method for the first time to biomolecular systems, our tests on peptide and mini-protein folding suggest five-fold increases in efficiency over a comparable method (manuscript in preparation). The success of the approach lies in mimicking the cooperative behaviour of birds flocking in how multiple copies of the system interact[2], leading to smoothing of the energy landscape and avoidance of local minima traps. We see the opportunity to adapt this tool to enhance the phase space volume sampled, by suitably modifying the coupling between system replicas. From these software modifications (Years 1-2 of the project), we will more accurately and cheaply model the structural and energetic features of large scale conformational changes, where the energy landscape is rough and barriers can be large compared to kT. This tool will then be applied to study of kinase conformation and function. Kinases are part of many vital signalling cascades and are exquisitely regulated. These proteins can adopt several conformations, of which two extremes are most commonly found: an open, active state and a closed, inactive state. These states feature a conserved Asp-Phe-Gly (DFG) motif within the activation loop: the active catalytic state has a DFG-in conformation, whereas a DFG-out conformation is not optimal for binding ATP substrate. To date, the pathway, energetics and intermediates between these states are not well understood. Neither is it known why some kinases do not appear to adopt a DFG-out conformation. This project will therefore apply this computational methodology to accurately model the energetics and structure of this large scale conformational rearrangement for selected kinases. DFG-in to DFG-out transitions will be driven using umbrella and swarm potentials for four kinases where both states are known (VEGFR2, c-Src, p38, Abl) and for three kinases which are known not to adopt a DFG-out structure (GSK3b, CDK1, one in-house kinase target). Hypothetical inactive structures for the latter kinases will be modelled by analogy (by the student at Johnson & Johnson during the first 3 months of the project). From these kinase simulations, we will identify key amino acids and molecular motifs along the transition pathway that could act as potential points of molecular recognition. We will then apply computer-aided design methods to screen commercial and Johnson & Johnson libraries for potential small molecules that can specifically recognise these protein conformations (Years 3-4). To provide validation for these in silico predictions, as well as a basis for further refinement of the model itself, promising small molecule hits will be assayed at Johnson & Johnson for kinase inhibitory activity, with the potential for further characterisation by structural biology and biophysical methods. Therefore, this interdisciplinary project seeks to develop a predictive computational tool to answer the fundamental questions of what energetic, structural and dynamic features underpin the active-to-inactive transition of many kinases and discern the underlying reason why some kinases do not adopt a DFG-out conformation. [1] Huber et al, J. Phys. Chem. A 1998, 102, 5943. [2] Kennedy et al, Proc. IEEE Intl. Conf. Neural Networks 1995, 4, 1942.

Neurotechnology is the use of insights and tools from mathematics, physics, chemistry, biology and engineering to investigate neural function and treat dysfunction; and additionally, the development of novel technology inspired by neuroscience. Brain-related illnesses affect more than two billion people worldwide, and add an annual burden which has been estimated to exceed $US 2.2 trillion. This is exacerbated by the aging societal demographic in most industrialized nations, including the UK: many brain disorders, such as dementia, are closely linked to age. There is a real need to solve this problem before it becomes an impossible burden for the economy to carry. The Centre for Doctoral Training in Neurotechnology for Life and Health will train a unique cadre of multidisciplinary researchers, who will combine an understanding of their neuroscience problem with skills in technology development, to make groundbreaking advances in our ability to treat brain disorders and to improve the quality of life and health in the UK. There is a strong need for such a pool of researchers in the UK now. Advances in treatments for brain disorders have to date relied largely upon a purely pharmaceutical approach, however the development of completely new drugs has slowed to a trickle as we have run into the "wall of complexity" where the cost of finding new drugs which do not have intolerable side effects becomes insurmountable. "High throughput" approaches have only pushed this wall back a year or two - as Peter Mueller of Vertex commented to us, "we need to shift our thinking from high throughput to high content". Our industry partners have emphasized to us that a new, engineering-driven approach is needed, to develop new solutions for uncovering that content. A key driver behind the development of this CDT bid has been the need for PhD level graduates with a multidisciplinary training, who bring with them both a detailed understanding of a translational neuroscience question, and the strong background in technology development needed to develop solutions. Our industry partners have all emphasized that the lack of availability of such researchers is currently a major limiting factor in their development prospects. By addressing this skills shortage, the CDT will have a major long-term impact on our ability to intervene in brain disorders, enhancing both academic and industrial research efforts to find solutions. "There is an unmet requirement for PhD graduates with a combined expertise in engineering and neuroscience and the proposed CDT in Neurotechnology will help to address this shortage" Jonas Gårding, Research & Physics Director Neuroscience, Elekta Instrument AB "The program that you propose to develop at the interface of neuroscience and engineering will produce PhD graduates with the potential to make major contributions to our research objectives" Kris Famm, PhD, VP Bioelectronics R&D, GlaxoSmithKline "We believe that the research conducted at the centre will have the potential to have a significant impact on the Parkinson's research field and ultimately on the lives of Parkinson's patients" Dr Kieran Breen, Director of Research and Innovation, Parkinson's UK.

We propose an End Use Energy Demand (EUED) Centre focused on Energy Epidemiology to be located at the multidisciplinary UCL Energy Institute (UCL-Energy), which undertakes research on energy demand and energy systems. Energy Epidemiology uses data and modelling to study energy use in the real world, with the aim of understanding the interactions of policy, technology, infrastructure, people and culture. The Centre for Energy Epidemiology (CEE) will: undertake primary data collection; advise on data collection; provide secure and ethical curation of a wealth of administrative, commercial and research data; link, develop and use innovative research methods; and support a structured research programme on energy demand intended to achieve a major reduction in UK carbon emissions. CEE will provide key research and policy insights at city, regional, national and international levels. It will support UK academics, policymakers and industry to research energy demand, by providing a cost-effective, secure and ethical bureau service for energy and related data. It will work closely with the new cross-government Energy Efficiency Deployment Office (EEDO) of DECC, the Energy Saving Trust, UK Energy Research Centre (UKERC) and the new Open Data Institute (ODI) to marshal and maximise the value of existing and very large future sources of energy-related data ('big data'), ensuring the greatest impact for evidence-based energy demand research. The Centre will initiate and be a key player in an international network of energy epidemiologists, sharing research methods and undertaking cross-cultural comparisons of policies and technologies to reduce energy demand and to help the UK to meet its carbon targets. UCL-Energy: - has a clear focus on energy demand and its interaction with energy supply systems - this has been the core focus of UCL-Energy since its launch, with full UCL support, 35 months ago. - is multi- and interdisciplinary with lawyers, economists, social scientists, engineers, physicists, psychologists, architects, mathematicians and policy analysts co-located in open plan offices facilitating collaborative work. It has successfully worked with researchers from anthropology, English literature and history on energy demand problems. - makes an impact by supporting policy makers and industry to both set and achieve UK carbon targets. Examples of such support include the Green Deal, CCC budgets, smart meter rollout, and the development of products for reducing energy demand. UCL-Energy is the only university centre that has officially advised DECC's new EEDO, whose focus is squarely on EUED. - undertakes research of the highest quality; its staff were recognised as "world leading" by two successive EPSRC Platform Grant reviews. Roughly half its staff were submitted in the Built Environment UoA (30), for which UCL received the highest percentage (35%) of internationally leading staff (4*) in the UK. It holds the grant for the only Centre for Doctoral Training in energy demand. - is not sector-specific; it covers all energy uses and applies methods across sectors e.g. transport and buildings. - is managed as a coherent centre - this is facilitated by placing all staff under a single budget centre with a clear management structure. UCL-Energy is advised and guided by a prestigious International Advisory Board with CEOs and directors from leading companies around the world. - has leveraged a wide range of funding. From an initial UCL investment of £680k, it has so far raised £10m of external funding, including £2m from industry. - has strong leadership - its Director, Professor Tadj Oreszczyn has established a new academic department at UCL in less than 3 years, advises government at senior level, is on the boards of key organisations and has written several strategic papers on the future direction of energy demand research. - has critical mass and sustainability: UCL-Energy has 80 staff and PhD students