Understanding fibroblast growth factor-heparan sulfate recognition by molecular dynamics approaches.

Glycosaminoglycans, linear periodic anionic polysaccharides composed of repeating disaccharide units, are highly heterogeneous with respect to their chemical composition, sulfation patterns, conformational, dynamic and functional properties. The "sulfation code," which links specific sulfation patterns of these molecules to their biological function, is a key concept for understanding their structure-function relationships. However, both experimental and computational approaches face significant challenges in deciphering this code. In this computational study, we focus on fibroblast growth factor-glycosaminoglycan interactions, which play crucial roles in numerous biologically relevant processes. First, we evaluate the sensitivity and predictive power of currently available computational protocols for studying these systems. We then rigorously investigate the effects of heparin 6-O-desulfation on its interactions with several fibroblast growth factors. We conclude that, depending on the 6-O-sulfation pattern and the length of the oligosaccharide, either predominantly electrostatic interactions or a more complex interplay between electrostatic and hydrophobic interactions determines the specificity of the resulting protein-glycosaminoglycan complex. Finally, we demonstrate that a previously developed coarse-grained model successfully reproduces both the structural and thermodynamic properties of the analysed molecular systems. The results obtained in this study may contribute to the understanding of the fundamental mechanisms underlying protein-glycosaminoglycan interactions and represent a further step toward deciphering the glycosaminoglycan "sulfation code."