The Influences of Sulphation, Salt Type, and Salt Concentration on the Structural Heterogeneity of Glycosaminoglycans

Abstract

The increasing recognition of the biochemical importance of glycosaminoglycans (GAGs) has in recent times made them the center of attention of recent research investigations. It became evident that subtle conformational factors play an important role in determining the relationship between the chemical composition of GAGs and their activity. Therefore, a thorough understanding of their structural flexibility is needed, which is addressed in this work by means of all-atom molecular dynamics (MD) simulations. Four major GAGs with different substitution patterns, namely hyaluronic acid as unsulphated GAG, heparan-6-sulphate, chondroitin-4-sulphate, and chondroitin-6-sulphate, were investigated to elucidate the influence of sulphation on the dynamical features of GAGs. Moreover, the effects of increasing NaCl and KCl concentrations were studied as well. Different structural parameters were determined from the MD simulations, in combination with a presentation of the free energy landscape of the GAG conformations, which allowed us to unravel the conformational fingerprints unique to each GAG. The largest effects on the GAG structures were found for sulphation at position 6, as well as binding of the metal ions in the absence of chloride ions to the carboxylate and sulphate groups, which both increase the GAG conformational flexibility.

In-Depth Molecular Dynamics Study of All Possible Chondroitin Sulfate Disaccharides Reveals Key Insight into Structural Heterogeneity and Dynamism

“…The Ramachandran plots showed characteristic preferences for both the 1→4- and 1→3-linked glycosidic bonds, which matched the available crystallographic data of free and protein-bound oligosaccharides ( Table S1 ). These results also correlated well with the published data using MD and NMR [ 27 , 31 , 32 , 33 , 36 , 37 ]. However, the collective analysis of all possible sequences revealed clear topological differences between the 1→4- and 1→3-linked sequences, each of which exhibited variations arising from the level of sulfation in two saccharide rings.…”

“…Understanding their structural and energetic preferences may offer better insight into designing oligomeric CS sequences that selectively bind proteins of interest. The literature contains several reports on the atomistic characterization of CS building blocks using X-ray crystallography [ 26 ], NMR [ 27 , 28 , 29 ], molecular modeling (MM) [ 30 ] and molecular dynamics (MD) [ 31 , 32 , 33 ]. Insights from the NMR and crystallographic studies have shown that the backbone orientations of the polymeric scaffold changes as sulfate groups are introduced at various positions.…”

Effect of Sulfation on the Conformational Dynamics of Dermatan Sulfate Glycosaminoglycan: A Gaussian Accelerated Molecular Dynamics Study

“…On the other hand, computational techniques, such as MD, can offer significant insights into the dynamics of GAG chains and the molecular recognition of proteins by GAGs . Recently, the effect of sulfation and cations on the conformational properties of disaccharides of CS and HS was studied through atomistic MD simulations. , Different macroscopic hydrodynamic properties of more than a hundred residues-long heparin sulfate chain were estimated using coarse-grained simulations . Also, different long sequences such as nonsulfated conformational ensembles of 10- and 20-mers of GAG chains and a 48-monosaccharide HA oligomer with varying salt concentrations and temperature were also investigated using MD simulations.…”

Atomic-Resolution Experimental Structural Biology and Molecular Dynamics Simulations of Hyaluronan and Its Complexes

“…Detailed solvation shell analysis revealed specific interaction points that could be occupied by Na + , which induce glycosidic dihedral conformational change that cause hairpin-like turns that compact the chain [ 126 ] ( Figure 5 ). Finally, while Na + is more likely to form direct interactions with hyaluronan than is Mg 2+ , as discussed above, K + is even more likely than Na + to form direct interactions [ 127 ]. This arises from the larger ionic radius of K + compared to Na + that, combined with polymer rigidity limitations, makes direct K + bridging of carboxylate groups more likely than solvent-separated K + bridging [ 127 ].…”

“…Finally, while Na + is more likely to form direct interactions with hyaluronan than is Mg 2+ , as discussed above, K + is even more likely than Na + to form direct interactions [ 127 ]. This arises from the larger ionic radius of K + compared to Na + that, combined with polymer rigidity limitations, makes direct K + bridging of carboxylate groups more likely than solvent-separated K + bridging [ 127 ].…”