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Sequence-to-structure dependence of isolated IgG Fc complex biantennary N-glycans: a molecular dynamics study
Glycobiology ( IF 3.4 ) Pub Date : 2018-11-17 , DOI: 10.1093/glycob/cwy097
Aoife M Harbison 1 , Lorna P Brosnan 1 , Keith Fenlon 1 , Elisa Fadda 1, 2
Affiliation  

Fc glycosylation of human immunoglobulins G (IgGs) is essential for their structural integrity and activity. Interestingly, the specific nature of the Fc glycoforms is known to modulate the IgG effector function and inflammatory properties. Indeed, while core-fucosylation of IgG Fc-glycans greatly affects the antibody-dependent cell-mediated cytotoxicity function, with obvious repercussions in the design of therapeutic antibodies, sialylation can reverse the antibody inflammatory response, and galactosylation levels have been linked to aging, to the onset of inflammation, and to the predisposition to rheumatoid arthritis. Within the framework of a structure-to-function relationship, we have studied the role of the N-glycan sequence on its intrinsic conformational propensity. Here we report the results of a systematic study, based on extensive molecular dynamics simulations in excess of 62 μs of cumulative simulation time, on the effect of sequence on the structure and dynamics of increasingly larger, complex biantennary N-glycoforms isolated from the protein, i.e. from chitobiose to the larger N-glycan species commonly found in the Fc region of human IgGs. Our results show that while core fucosylation and sialylation do not affect the intrinsic dynamics of the unlinked N-glycans, galactosylation of the α(1–6) arm shifts dramatically its conformational equilibrium from an outstretched to a folded conformation. These findings are in agreement with and can help rationalize recent experimental evidence showing a differential recognition of positional isomers in glycan array data and also the preference of sialyltransferase for the more accessible, outstretched α(1–3) arm in both isolated, and Fc-bound N-glycans.

中文翻译:

分离的IgG Fc复合物双天线N聚糖对序列的结构依赖性:分子动力学研究

人免疫球蛋白G(IgG)的Fc糖基化对其结构完整性和活性至关重要。有趣的是,已知Fc糖型的特定性质可调节IgG效应子功能和炎性特性。确实,尽管IgG Fc-聚糖的核心岩藻糖基化会极大地影响抗体依赖性细胞介导的细胞毒性功能,在治疗性抗体的设计中会产生明显影响,但唾液酸化可以逆转抗体的炎症反应,而且半乳糖基化水平与衰老有关,导致炎症发作,以及类风湿关节炎的易感性。在结构与功能关系的框架内,我们研究了N的作用-聚糖序列的内在构象倾向。在这里,我们报告了一项系统研究的结果,该结果基于超过62μs累积模拟时间的广泛分子动力学模拟,研究了序列对从蛋白质中分离出的越来越大的复杂双天线N型糖型的结构和动力学的影响,即从壳二糖到通常在人IgGs Fc区中发现的较大的N-聚糖种类。我们的结果表明,核心岩藻糖基化和唾液酸化不会影响未连接N的内在动力学。-聚糖,α(1–6)臂的半乳糖基化将其构象平衡从伸展构象急剧转变为折叠构象。这些发现与最近的实验证据相吻合,并且可以使这些实验证据合理化,这些证据表明在聚糖阵列数据中对位置异构体的区别识别以及唾液酸转移酶对于分离的和Fc-中更易伸张的α(1-3)臂的偏爱。结合的N-聚糖。
更新日期:2018-11-17
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