Rationalising glycomics with GPU-accelerated equilibrium simulations: a novel route to 3D-structure biological function and molecular design

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Carbohydrates, amino acids, nucleic acids and lipids constitute the fundamental building blocks of life. Although carbohydrates were the first of these to be extracted from living organisms and characterised, our understanding of protein and nucleic acid biological function is far advanced, which is, in part, due to the excellent progress made in the 1950s on probing the structure of crystallised biological matter with x-rays. By investigating the geometries adopted by amino acids and nucleic acids, Watson, Crick, Pauling, Phillips and others theorised that biological function is a manifestation of microscopic shape, which drove a revolution in Biochemistry: the realisation that proteins comprise a string of amino acids folded into specific functional shapes and work as micro-machines. It also led to discovery of the DNA-double helix, which carries our genetic information and is the progenitor of Molecular Biology and Genetics. Unfortunately, a similar revolution has not occurred in our understanding and harnessing of carbohydrates, for example, although the heparin carbohydrate has been routinely used in surgical procedures for almost a century, the mechanism of action has only recently begun to be understood. The problem is that carbohydrates do not crystallise readily and other techniques to investigate their microscopic shape have not been developed. Consequently, the relationship between carbohydrate composition and function is tenuous. Carbohydrates, therefore, represent a major unexplored frontier in Biochemistry and due to their fundamental industrial importance (e.g., food, paper, wood, pharmaceuticals, biomaterials) any breakthrough in understanding this relationship would certainly lead to another revolution in biotechnology. This research is driving toward providing this important link between carbohydrate composition and function by developing new techniques for investigating their microscopic shape. Rather than using x-rays, we are using precise and extensive computer simulations, advanced methods for refining pure carbohydrates and a molecular microscope based on magnetic resonance (similar to MRI-scanners found in hospitals) to achieve this goal. To date our research has focused on unravelling some of the mysteries surrounding the large polymeric carbohydrate molecules called glycosaminoglycans (GAGs), which fill the space between cells, bonding them together, conferring strength to organs, joints and skin, while allowing our bodies to grow and change. Microscopically, carbohydrate molecules are composed of chemical rings, joined together to form polymeric chains. We found that to accurately describe the shape of these molecules we need to understand both what is happening around the connection joints between these rings and also how the rings flex dynamically. Computer simulations of carbohydrates, which take into account thousands of interactions with solvent water, have so far managed to investigate the joints, but up until now limitations in computer hardware has not permitted an investigation into ring flexing because it happens on timescales that are hundreds of times longer. We overcame this problem using graphics processors (hardware used for computer gaming) to dramatically speed-up simulations and provide insight into the GAG heparan sulphate, an anticoagulant similar to heparin that lines blood vessels. It has revealed that ring flexing is central to carbohydrate function and that absence of ring flexing leads to regions that are stiffened, which consequently interact with other molecules in the body. We now plan to research and test this hypothesis further and determine whether this ring flexing behaviour is central to the function of other GAGs, such as those found in cartilage and skin, whether it is important in other human and plant carbohydrates and whether it can be used for understanding how to design novel pharmaceuticals and biomaterials based on carbohydrates.