Glycosylation is among the most common post-translational modifications in proteins, although it is observed in only about 10% of all the protein structures in protein data bank (PDB). Modifications of sugar composition in glycoproteins profoundly impact the overall physiology of the organism. One such example is the development of insulin resistance, which has been attributed to the removal of sialic acid residues from N-glycans of insulin receptor (IR) from various experimental studies. How such modifications affect the glycan-glycoprotein dynamics, and ultimately their function is not clearly understood to date. In this study, we performed molecular dynamics simulations of glycans in different environments. We studied the effects of removal of sialic acid on the glycan, as well as on the dynamics of leucine-rich repeat L1 domain of the IR ectodomain. We observed perturbations in L1 domain dynamics as a result of the removal of sialic acid. The perturbations include an increase in the flexibility of insulin-binding residues, which may affect insulin binding with IR. These changes are accompanied by perturbations in glycan–protein interactions and perturbation of long-range allosteric dynamics. Our observations will further aid in understanding the role of sugars in maintaining homeostasis and how changes in glycan composition may lead to perturbations in homeostasis, ultimately leading to conditions such as insulin resistance.

中文翻译：

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聚糖组成变化对糖蛋白动力学的影响：N-聚糖对胰岛素受体的影响

糖基化是蛋白质中最常见的翻译后修饰之一，尽管在蛋白质数据库 (PDB) 中仅约 10% 的蛋白质结构中观察到糖基化。糖蛋白中糖成分的改变深刻地影响了生物体的整体生理机能。一个这样的例子是胰岛素抵抗的发展，这归因于从N中去除唾液酸残基-来自各种实验研究的胰岛素受体 (IR) 聚糖。迄今为止，此类修饰如何影响聚糖-糖蛋白动力学以及最终它们的功能尚不清楚。在这项研究中，我们对不同环境中的聚糖进行了分子动力学模拟。我们研究了去除唾液酸对聚糖的影响，以及对 IR 胞外域的富含亮氨酸的重复 L1 域的动力学。由于唾液酸的去除，我们观察到 L1 域动力学的扰动。干扰包括增加胰岛素结合残基的灵活性，这可能会影响胰岛素与 IR 的结合。这些变化伴随着聚糖-蛋白质相互作用的扰动和远程变构动力学的扰动。