Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Khandwa Road, Indore 453552, Madhya Pradesh, India.
J Phys Chem B. 2022 Jun 2;126(21):3852-3866. doi: 10.1021/acs.jpcb.2c01807. Epub 2022 May 20.
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 (, , and ) 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 -acetylgalactosamine (-GalNAc). Here, -GalNAc is linked to IdoA via β(1-4), while IdoA is linked to -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., ), the ring flip between two chair forms vanished for IdoA. The dynamic cross-correlation analysis reveals that the anticorrelation motions in are reduced significantly compared to or . 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.
糖胺聚糖 (GAGs) 是带负电荷的生物聚合物，存在于细胞表面，是蛋白聚糖的一部分。GAGs 的生物活性取决于硫酸化模式。在我们的研究中，我们考虑了三条带有递增硫酸化程度的十八糖硫酸皮肤素 (DS) 链（、和），通过 10 μs 长的高斯加速分子动力学模拟来阐明 GAG 单元和其链构象上硫酸化的作用。DS 由重复的二糖单元组成，包括艾杜糖醛酸 (IdoA) 和 N-乙酰半乳糖胺 (-GalNAc)。在这里，-GalNAc 通过 β(1-4)与 IdoA 相连，而 IdoA 通过 α(1-3)与 -GalNAc 相连。随着硫酸化程度的增加，DS 结构变得更加刚性和线性，这从均方根偏差 (RMSD) 和末端到末端距离的分布中可以明显看出。主链的四糖连接区在糖苷键方面表现出刚性构象。我们观察到，在硫酸化后（即），IdoA 两个椅式构象之间的环翻转消失了。动态互相关分析表明，与或相比，的反相关运动显著减少。硫酸化程度的增加会产生相对更稳定的氢键网络，包括与相邻单糖的水桥接。尽管 GAG 链具有有利的线性结构，但我们的研究也预测了与不同的构象状态相关的几个显著弯曲，这可能在 DS 的功能中发挥重要作用。全局构象与微尺度参数（如构象和水介导的氢键）之间的关系决定了 GAG 的整体构象空间。总的来说，本研究提供的 DS 链的原子细节将有助于理解它们的功能和机械作用，以及开发新的生物材料。
