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

Abstract

Glycosaminoglycans (GAGs) are anionic biopolymers present on cell surfaces as a part of proteoglycans. The biological activities of GAGs depend on the sulfation pattern. In our study, we have considered three octadecasaccharide dermatan sulfate (DS) chains with increasing order of sulfation ( dp 6s, dp 7s, and dp 12s) to illuminate the role of sulfation on the GAG units and its chain conformation through 10 μs-long Gaussian accelerated molecular dynamics simulations. DS is composed of repeating disaccharide units of iduronic acid (IdoA) and N-acetylgalactosamine (N-GalNAc). Here, N-GalNAc is linked to IdoA via β(1–4), while IdoA is linked to N-GalNAc through α(1–3). With the increase in sulfation, the DS structure becomes more rigid and linear, as is evident from the distribution of root-mean-square deviations (RMSDs) and end-to-end distances. The tetrasaccharide linker region of the main chain shows a rigid conformation in terms of the glycosidic linkage. We have observed that upon sulfation (i.e., dp 12s), the ring flip between two chair forms vanished for IdoA. The dynamic cross-correlation analysis reveals that the anticorrelation motions in dp 12s are reduced significantly compared to dp 6s or dp 7s. An increase in sulfation generates relatively more stable hydrogen-bond networks, including water bridging with the neighboring monosaccharides. Despite the favorable linear structures of the GAG chains, our study also predicts few significant bendings related to the different puckering states, which may play a notable role in the function of the DS. The relation between the global conformation with the micro-level parameters such as puckering and water-mediated hydrogen bonds shapes the overall conformational space of GAGs. Overall, atomistic details of the DS chain provided in this study will help understand their functional and mechanical roles, besides developing new biomaterials.

Sulfation Effects of Chondroitin Sulfate to Bind a Chemokine in Aqueous Medium: Conformational Heterogeneity and Dynamics from Molecular Simulation

“…Such shortening of free-energy surface region was previously found when the sulfate group was present in IdoA of the other GAGs like DS. 33 Clearly, changes in glycosidic space in terms of principal minima are noted in the complexed form than in the corresponding free form of the CS-T. As compared to the free CS, the different conformational regions of FEL covered by the CS molecules increase upon complexation with the receptor protein. Importantly, upon complexation with CXCL8 multiple minimum regions are noticed.…”

“…Non-sampling of the 1 C 4 state for GalNAc was observed in previous experimental and computational studies. 58,33 For GalNAc, the principal minimum suggested the most preferred 4 C 1 conformers in both free and complexed forms irrespective of the sulfation patterns. The skew-boat conformations of GalNAc of free CS molecules are in significantly higher energy states relative to the 4 C 1 state.…”

Glycosaminoglycans: What Remains To Be Deciphered?

“…However, the possible misinterpretations of the strength and stability of the complexes are not frequently discussed. Gaining accuracy requires more complex and time-consuming MD simulations to get additional insights into the binding stability, the role of nonionic and polar residues, and bridging water’s influence on GAG conformations. , Binding energies can be calculated from MD simulations following either the linear interaction energy approximation or the Poisson–Boltzmann Surface­(PBSA)/generalized Born, umbrella sampling, and Potential of Mean Force (PMF) methods and compared with experimental data. Free-energy-end point methods are not even close to chemical accuracy for tight binding of drugs, let alone for highly flexible multicontact-based interactions of low affinity.…”

Chitosan as a Canvas for Studies of Macromolecular Controls on CaCO3Biological Crystallization

“…Studies have traditionally focused on the carboxyl groups associated with CaCO 3 organic matrices, making important contributions. Given that sulfate and phosphate groups can have significant effects on ion binding and ion solvation as structure directing agents, − the higher charge density of these species may contribute as much as or more than carboxyls to mineralization.…”