New Multiscale Tools for Protein Physics: Thermal Protein Dynamics in Signalling and Allostery.

Proteins are natures molecular machines. Built out of an alphabet of only 24 small molecules joined into long chains, in folded-form they constitute the structures, scaffolds, signalling pathways, transport systems, motors and cargo transporters of the tissues and cells of all living things. Since their exquisitely evolved and precise structures have been elucidated through X-ray scattering, the emphasis has been on understanding how these structures lead to function (such as binding to specific small molecules at special pockets and clefts). More recently however, it has become clear that the constant dynamical excitations of proteins, a natural consequence of a finite-temperature environment, also play a vital role in function. Data from careful thermal analysis, and also from magnetic resonance measurements, have shown how binding events at proteins can change the nature of their internal ceaseless wobbling considerably. Furthermore, recent work by the applicants has shown how mathematical and physical models of proteins can analyse these motions and identify how their changes are used to generate vital signals within protein networks. These control all aspects of cell function, so understanding them is very important in biology.The goal of this project is to build on the initial foundations of coarse-grained protein modelling and link the global models of entire protein molecules to their atomistic structure in a predictive way. The physicists and chemists will work with biologists in validating these new tools on a series of model protein systems. By making tiny changes in the proteins ( mutations ), predictions of the models can be tested by experiments. A particular goal is to use the technique to design a new protein with entirely new allostetric properties that have been engineered into the protein on the basis of the course-grained model. This will demonstrate a potential route to commercialisation of the science in biotechnology.At the end of the project, a systematic analytical tool for global protein dynamics will be available to the community, both academic and industrial.

This multi-disciplinary project will produce high quality results in the areas of mathematical and physical modelling, protein molecular biology, and structural biology and will be of interest to the whole spectrum of natural science. Results will be published wherever possible in high quality peer-reviewed journals, disseminated through presentations at conferences, and via a lab web-site. Our work will be of interest to the biotechnology industry. The most immediate application with the potential for wealth creation is in the design of metabolite sensitive proteins whose regulatory properties can be manipulated to improve the yield of industrially important bacterial products. The applicants have close links through the Biophysical Sciences Institute (BSI) at Durham (established in 2007 with the aim of developing research combining all the physical sciences to help solve challenges within the life sciences). All of the applicants have an excellent track record in interdisciplinary research and are frequently invited to speak at international conferences. This proposal will therefore have academic impact in many scientific fields. It is anticipated that this work will challenge other researchers to explore opportunities for applying their particular skills to biological issues. The BSI is developing a UK network of contacts with complementary groups (UCL, Leeds, Nottingham, Edinburgh, Dundee and Glasgow) and this project will contribute to an increasingly co-ordinated UK effort in Biological Physics. In a wider international context, the project represents a major UK contribution to the growing field of functional protein dynamics. The work will stimulate collaborations with, and promote advances in research groups in several related areas e.g. NMR techniques, complementary modelling, and neutron scattering. A principal impact of the project will therefore be the collaborative engagement with a wider community of biological and biotechnological scientists, who will use and develop our tools and methodology across a wide range of protein science into the industrial arena. Beyond the academic community the team has a strong record in the broader dissemination of science and the protection of any intellectual property that might be developed. The University's Technology Transfer Office will protect any novel results with potential commercial impact. The impact areas here could be very broad. The team have previously had collaborations with large industrial organisations and Durham University is an academic member of the UK Polymer IRC, an organization of 4 academic and over 20 industrial partners that holds a regular series of Knowledge Transfer activities. Through their network of contacts the results will thus be presented to members of the industrial community to help explore areas of application that are at present not well known. During the project we will also arrange at least one multidisciplinary international meeting dedicated to the subject of protein dynamics from theoretical, experimental and biological perspectives with the aim of stimulating further discussion and research in the area. The project will also play a significant role in helping to train the next generation of researchers with inter-disciplinary skills capable of working at the crucial life-science interface. The researchers in the project will be exposed to a unique combination of mathematical theory and physical and biological experimentation. They will thus learn the language and method of working within both disciplines. Being able to explain complex concepts from your own specialist field to those of another scientific discipline is of growing importance and this project will provide an excellent route to learning these skills for the researchers involved.