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

Suman Samantray,Olujide O Olubiyi,Birgit Strodel

doi:10.3390/ijms222111529

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.

Highlights

Glycosaminoglycans (GAGs), with their presence in the extracellular matrix [1], blood vessels, and tissues in the human body, play an important role in cellular signaling activity, anticoagulation, and angiogenesis and have been implicated in various other biological processes [2,3]
Chondroitin and hyaluronate are used in different pharmaceutical and nutraceutical formulations for the treatment of osteoarthritis [8,9,10,11]; heparin and its mimetics are used as anticoagulants for treating thrombosis; keratan sulphate is incorporated in ophthalmic products for treating certain eye defects and as biomarker for female genital tract carcinoma [12]
The obtained root-mean-squared deviation (RMSD) variations were in the range of 0.4–0.6 nm, regardless of the salt type and concentration, which allowed us to conclude that the GAGs are quite flexible, especially when compared to folded proteins and considering their relatively short chain length

Summary

Introduction

Glycosaminoglycans (GAGs), with their presence in the extracellular matrix [1], blood vessels, and tissues in the human body, play an important role in cellular signaling activity, anticoagulation, and angiogenesis and have been implicated in various other biological processes [2,3] They are large unbranched polymers of differentially sulphated carbohydrate units often found covalently attached to proteins (except hyaluronic acid) in proteoglycans. An inspection of the GAG interactome indicates their involvement in more than just physiological processes: they have been found to play a role in various pathological conditions Their interaction with amyloidogenic proteins implicates them as participants in the pathogenesis of amyloid-related neurodegenerative disorders, such as Alzheimer’s disease, type-2 diabetes, Parkinson’s disease, and prion diseases [6,7]. Beyond their use in different capacities as a replacement therapy, recent studies have suggested additional roles as possible therapeutic agents in inhibiting cell invasion by viruses causing severe acute respiratory syndrome (SARS) diseases [13,14]

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Conclusion