Faculty of Chemistry, University of Gdansk, ul. Wita Stwosza 63, 80-308 Gdańsk, Poland.
Biomolecules. 2023 Jan 28;13(2):247. doi: 10.3390/biom13020247.
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.
糖胺聚糖（GAGs）是一类含有二糖重复单元的线性阴离子周期性多糖。这些分子与细胞外基质中的各种蛋白质相互作用，从而参与生物化学上至关重要的过程，如影响组织再生以及癌症、阿尔茨海默病或帕金森病发生的细胞信号转导。由于其灵活性、周期性和化学异质性，通常被称为“硫酸化代码”，GAGs 无论是在实验还是计算方面都是具有挑战性的分子。GAG 研究中的一个关键问题是它们分子间相互作用的特异性。在这项研究中，我们朝着破译硫酸软骨素 4,6（CS4, CS6，其中数字对应于 NAcGal 残基中硫酸化的位置）和硫酸皮肤素（DS）的“硫酸化代码”迈出了一步，DS 与 CSs 的不同之处在于存在 IdoA 酸而不是 GlcA。我们使用基于分子动力学的描述符，严格研究了这两种 GAGs 的二聚体、四聚体和六聚体形式。我们的数据清楚地表明，CS4、CS6 和 DS 在结构、构象和动态特性方面存在显著差异，这有助于理解这些分子在与蛋白质结合时如何有所不同，这可能对基于 GAG 的再生医学药物设计策略具有实际意义。
