Molecular Dynamics-Based Comparative Analysis of Chondroitin and Dermatan Sulfates

Glycosaminoglycans (GAGs) are a class of linear anionic periodic polysaccharides containing disaccharide repetitive units. These molecules interact with a variety of proteins in the extracellular matrix and so participate in biochemically crucial processes such as cell signalling affecting tissue regeneration as well as the onset of cancer, Alzheimer's or Parkinson's diseases. Due to their flexibility, periodicity and chemical heterogeneity, often termed sulfation code, GAGs are challenging molecules both for experiments and computation. One of the key questions in the GAG research is the specificity of their intermolecular interactions. In this study, we make a step forward to deciphering the sulfation code of chondroitin sulfates-4,6 (CS4, CS6, where the numbers correspond to the position of sulfation in NAcGal residue) and dermatan sulfate (DS), which is different from CSs by the presence of IdoA acid instead of GlcA. We rigorously investigate two sets of these GAGs in dimeric, tetrameric and hexameric forms with molecular dynamics-based descriptors. Our data clearly suggest that CS4, CS6 and DS are substantially different in terms of their structural, conformational and dynamic properties, which contributes to the understanding of how these molecules can be different when they bind proteins, which could have practical implications for the GAG-based drug design strategies in the regenerative medicine.

Automated summary

Glycosaminoglycans (GAGs) are linear anionic polysaccharides that interact with proteins in the extracellular matrix and play important roles in cell signaling, tissue regeneration, and diseases such as cancer, Alzheimer's, and Parkinson's. This study investigates the structural and dynamic properties of chondroitin sulfates-4,6 (CS4, CS6) and dermatan sulfate (DS), revealing substantial differences between these GAGs. Understanding these differences can have practical implications for designing GAG-based drugs in regenerative medicine.