位阻效应
化学
氢键
单体
分子间力
机制(生物学)
分子动力学
生物物理学
α-突触核蛋白
立体化学
分子
计算化学
生物
帕金森病
疾病
病理
哲学
有机化学
认识论
聚合物
医学
作者
Kai Wu,Dechang Li,Peng Xiu,Baohua Ji,Jiajie Diao
出处
期刊:Physical Biology
[IOP Publishing]
日期:2020-12-01
卷期号:18 (1): 016002-016002
被引量:7
标识
DOI:10.1088/1478-3975/abb6dc
摘要
Toxic abnormal aggregation of α-synuclein (α-Syn) is a feature of Parkinson's disease. Several biochemical and biophysical studies have demonstrated that many post-translational modifications (PTM) of α-Syn could distinctly alleviate its oligomerization-mediated toxicity. Recently, a compelling link is emerging between the PTM O-GlcNAcylation (O-GlcNAc) and protein aggregation, yet the underlying molecular mechanism remains unclear. Based on the all-atom molecular dynamics simulations, we found that O-GlcNAc modifications can suppress the process of oligomerization of α-Syn aggregates via a steric effect-the additional O-linked glycosyl group disrupts the formation of hydrogen bonds (H-bonds) between α-Syn monomers. Besides, we proposed a theoretical model to further capture the physical mechanism of α-Syn aggregation/disaggregation in the absence/presence of O-GlcNAc-modified α-Syn. Our findings unveil the molecular mechanism of the O-GlcNAc-induced inhibition of α-Syn oligomerization, which may help to understand how O-GlcNAc prevents the oligomerization of other proteins and provides the guideline for the development of O-GlcNAc-based therapeutic strategies in neurodegenerative diseases.
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