With DNA (RNA) and proteins, two major biopolymers, major scientific effort has been aimed at understanding how sequence dictates function. The third major biopolymer is the polysaccharides. One of the most important groups of polysaccharides, in terms of its influence on important biological phenomena, is the heparin/hepamn sulfate-like glycosaminoglycans (HSGAGs). HSGAGs are intimately involved in important processes like embryo development, blood clotting, and new vessel growth. We know that HSGAGs bind to proteins and affect their activity, thus influencing cell functions but we do not know how HSGAGs carry out their important biological functions. Our preliminary studies point out to exciting properties associated with HSGAG upon protein binding. While the overall helical structure is maintained in the protein-bound HSGAGs, a """"""""kink"""""""" in the helical axis is induced upon protein binding. This kink is formed by a change in the backbone torsion angles, which cause local conformational changes in the HSGAG structure. Further, the ability of the iduronic acid in HSGAGs to adopt multiple ring conformations enhances the formation of the kink and governs the nature and degree of kink in the helical axis of the FGF-bound HSGAG oligosaccharide. The link appears to provide a structural 'signature"""""""" for sequence specific HSGAG-protein interactions. These conformational changes in HSGAG induced upon protein binding are reminiscent of those occurring in DNA, where, as a rule protein binding causes over winding/ under winding or]kinked structures in DNA for maximum contact and specificity. Thus, in order to really understand the molecular basis of specificity of HSGAG-protein interaction, it becomes essential to focus on the HSGAG and protein structure and conformation. With FGF as a model system, the goals of the next phase of theR0 are to elucidate the molecular principles [structural and conformational] aspects of both HSGAG and FGF. We believe that this study will shed insights into the fundamentals of HSGAG-protein interactions enabling us to propose broader concepts on HSGAG-protein interactions at the molecular level. This becomes especially important in light of the explosive growth of recent studies that not only implicate HSGAGs in several important biological processes, but also attribute their involvement in these functions in a sequence specific manner.
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