Modelling Carbohydrate Solution Structure Using a Novel Combined Experimental-Computational Strategy

Our ability to make new discoveries in biochemistry and to develop new pharmaceuticals, advanced materials, energy sources and foodstuffs is increasingly dependent on our understanding of how biomolecules work at the molecular level. This in turn depends on our understanding of the structure of these biomolecules, and how their structures control their functions. This has been the guiding principle that has resulted in many of the advances in medicine, biology, chemistry and materials science of the last few decades. These advances have owed much to the structural information that has been obtained for proteins and nucleic acids by X-ray crystallography and NMR spectroscopy, and which has revolutionised our view of how life works. Unfortunately, these techniques are far more difficult to apply to the main class of biomolecules, carbohydrates. As a result, even though carbohydrates constitute around 99% of the biomass of our planet and perform an almost limitless number of roles in living systems, from algae to plants to humans, we don't really understand how they work in the same way that we do for proteins and DNA. The lack of definitive data means there is still considerable debate as to how we even define structure in carbohydrate polymers. In order to best capitalise on the great potential of carbohydrates in both science and industry we will have to understand to a much greater level of detail the molecular principles that govern their assembly, organisation and interactions with other molecules. This will require new approaches to studying carbohydrate structure.

In order to meet this urgent requirement we will develop a combined computer modelling and spectroscopic lab-based approach to characterising the structures of carbohydrates, from simple sugars to key carbohydrate polymers known to be involved in regulating biological functions. Three components to the project will combine to generate a uniquely incisive new tool for glycobiology. First, high level quantum chemistry calculations will provide highly detailed spectra that are sensitive to all aspects of carbohydrate conformation, so allowing us to identify subtle structural differences. Secondly, as recent work shows that hydration plays an important role in controlling carbohydrate conformation, we will use molecular dynamics simulations to identify which structures are formed by each carbohydrate in the solvated environments in which they are found naturally and how they interact with the water molecules around them. Thirdly, we will measure highly detailed Raman spectra to provide the gold standard benchmarks required to prove that our calculations and modelling are correct. This will also provide us with a rigorous standard against which to validate the novel computer modelling. Although this development of new computational tools will be focused on the structures and behaviour of carbohydrates, the end product will also be widely applicable to all other biomolecules, particularly proteins and nucleic acids. The challenges we will overcome are those faced by researchers attempting to model how other molecules behave, e.g. how stable is the structure? how do its components interact? how do interactions with solvent water or other molecules affect its shape? Because our novel computational tools are generic they will be able to provide new insights into many other areas of research, such as protein-ligand interactions and DNA-drug molecule binding.

Carbohydrates are the most abundant and structurally diverse class of biomolecules, with roles in almost every type of biological process, and are a key resource for the UK and global economies. Carbohydrates are used as antibiotics and therapeutics, as scaffolds for drug discovery and as glycomimetics, growing components of the global drug market worth $US 825 billion. Our project is directly relevant to EPSRC through;
i) Grand Challenge of Systems Chemistry: Exploring the Chemical Roots of Biological Organisation as we will develop the understanding of the structural principles at the molecular level that direct glycoprotein function and behaviour. Our project design will provide a methodology to clarify the chemical principles for carbohydrate-water interactions at the molecular level.
ii) Energy. Carbohydrates are a key energy source both for biological systems and for biofuels.
iii) Next Generation Healthcare. Our project is designed to investigate the general principles of structure and function in carbohydrates and glycans, so can inform on the principles underlying carbohydrate-related research directions (e.g. cancer, bone and cartilage growth, tissue repair, site-directed drug delivery).
The same structural precepts determine the roles of proteoglycans and glycosaminoglycans in maintaining integrity of the extracellular matrix, a target for research into iv) Ageing - Lifelong Health and Wellbeing.
A more detailed understanding of carbohydrate structural parameters will lead to a rejuvenation of the structure-function paradigm (understand the structure of a molecule in order to understand its function) in carbohydrate chemistry. The techniques we will develop will be applicable to all carbohydrates, so benefiting all researchers in academia, healthcare and industry interested in understanding their structures, which will lead to much greater understanding and use of carbohydrates in the future.

Developing more realistic force fields will also assist;
v) Academic researchers. Many academics, including PhD students and PDRAs in universities and research institutes, use force fields to carry out their atomistic simulations. Their work will benefit from enhanced accuracy and reliability researchers working in fields such as energy storage and even food science.
vi) Companies using molecular modelling. Many companies recognise the increasing role of computation in the future since cheaper hardware is guaranteed to emerge during the coming decades. As users of more reliable software they will make better predictions, which is vital for the trustworthiness of molecular modelling. We will test our product on specific cases that were not satisfactorily solved by existing packages.
vii) UK plc and employment. In time of contraction it is important to invest in brand new technologies because they will emerge with invigorated impact. Novel and better technologies create longer term and sustainable wealth. Molecular modelling methods are quoted (e.g. a Pathfinder sponsored market assessment we commissioned in connection with a different grant) as being significant tools in nanoscale R&D across a variety of industries.
viii) EPSRC itself and Policy-makers. On p.16 of the Int. Review of UK Chemistry Research (April 09) the reviewers complain that "In the area of theory and computation, no provision seems to have been made to encourage the development of new algorithms and new ideas to bring to full fruition the utilisation of the next generation ... machines". The current application will help raise the current international standing of theoretical and computational chemistry in the UK. This will benefit EPSRC at the next International Review.

The staff employed on this project will benefit from unique interdisciplinary training in future growth areas (high level computations, carbohydrates, advanced spectroscopy). They will not be able to obtain a mix of these skills and opportunities anywhere else in the world.