Molecular dynamics simulation of the aggregation and folding mechanism of α-synuclein 47-56 in core peptide fragments induced by α-synuclein pentamer template.

IF 2.7 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Ruijuan Liu, Xuewei Liu
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引用次数: 0

Abstract

The misfolding of intrinsically disordered α-synuclein protein, which can form β-sheet-rich fibrillar amyloid structures, is closely associated with Parkinson's disease (PD). The peptide α-synuclein 47-56 has been identified as the toxic core of α-synuclein and plays a pivotal role in the aggregation and misfolding processes of this protein. Investigating the template induction behavior of this peptide is crucial for elucidating the molecular mechanisms underlying α-synuclein misfolding and aggregation. To explore the molecular mechanism of the peptide α-synuclein 47-56, guided by the α-synuclein pentamer template, we conducted a 400 ns molecular dynamics simulation. In this simulation, the peptide α-synuclein 47-56 was positioned on both sides of the α-synuclein pentamers. Our results demonstrate distinct elongation characteristics of the peptide α-synuclein 47-56 on the two sides of the pentamer. The β-sheet structure readily formed on the left side of the α-synuclein pentamer, facilitating template induction. In contrast, the formation of β-sheet secondary structures was hindered on the right side of the α-synuclein pentamer. Furthermore, our analysis reveals that hydrogen bonding, electrostatic interactions, and van der Waals forces between the α-synuclein pentamer and monomer are crucial for β-sheet extension. Notably, we identified the α-synuclein 49-53 region as a key peptide segment in this process.

α-synuclein五聚体模板诱导α-synuclein 47-56在核心肽片段聚集折叠机制的分子动力学模拟。
内在无序α-突触核蛋白的错误折叠可形成富含β-薄片的纤维状淀粉样蛋白结构,与帕金森病(PD)密切相关。肽α-synuclein 47-56已被确定为α-synuclein的毒性核心,并在该蛋白的聚集和错误折叠过程中起关键作用。研究该肽的模板诱导行为对于阐明α-突触核蛋白错误折叠和聚集的分子机制至关重要。为了探索α-synuclein 47-56肽的分子机制,我们以α-synuclein五聚体模板为指导,进行了400 ns的分子动力学模拟。在本次模拟中,肽α-synuclein 47-56位于α-synuclein五聚体的两侧。结果表明,α-synuclein 47-56在五聚体两侧具有明显的延伸特性。α-突触核蛋白五聚体左侧容易形成β-片结构,有利于模板诱导。相反,α-突触核蛋白五聚体右侧的β-片二级结构的形成受到阻碍。此外,我们的分析表明,α-突触核蛋白五聚体和单体之间的氢键、静电相互作用和范德华力对β-薄片的延伸至关重要。值得注意的是,我们发现α-synuclein 49-53区域是这一过程中的关键肽段。
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来源期刊
Journal of Biomolecular Structure & Dynamics
Journal of Biomolecular Structure & Dynamics 生物-生化与分子生物学
CiteScore
8.90
自引率
9.10%
发文量
597
审稿时长
2 months
期刊介绍: The Journal of Biomolecular Structure and Dynamics welcomes manuscripts on biological structure, dynamics, interactions and expression. The Journal is one of the leading publications in high end computational science, atomic structural biology, bioinformatics, virtual drug design, genomics and biological networks.
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