We have prepared several GAG small molecules, heparan sulfate trisaccharides, models of the regular region of heparin; and tetrasaccharides models of chondroitin sulfate and hybrid structures containing dermatan sulfate, CS-DS. We solved their 3D structures in solution by NMR and explore their interaction with growth factors, FGF-1 and Midkine, using transient NMR techniques to solve the bound conformations of the ligands.<br/>Our results confirmed the importance on the binding into the main site of FGF-1 of the sulfonate group in position 6 of the reducing end glucosamine. Also the potential addition “up-down” interactions when extra charges were available at the external side of the carbohydrate. In addition the use of this library revealed the relative importance of the additional charges. The results also confirmed the existence of additional binding sites around the protein surface.<br/>We also studied the interaction of CS or CS-DS with Midkine using the same methods. In this case the topology of the peptide is considerably different as MK can be considered an IDP protein. The binding of the unprotected tetrasaccharides wrapped by the protein keep the same structure that in solution, but display contacts with the two structured domains on Mk bearing aromatic aminoacids. The importance of the non-polar or CH-pi interactions arise when the interactions of the partially deprotected precursors where measured and were stronger.

Insights into the interactions between synthetic GAG and Growth Factors (FGF-1 and Midkine)

254th National Meeting (2017)

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