折叠和内在无序区域含有蛋白质凝聚物的多尺度模拟
Lyudmyla Dorosh1, Holger Wille2, Maria Stepanova1
1Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, Canada.
Biophysical journal
|October 15, 2025
概括
这项研究引入了一种多尺度模拟框架,用于模拟蛋白质错折疾病. 综合方法揭示了离子度和模拟参数如何影响疾病相关蛋白质的蛋白质组合和动态.
科学领域:
- 计算生物物理学和结构生物学.
- 研究蛋白质错误折叠和聚合机制.
背景情况:
- 蛋白质错误折叠疾病,例如涉及TDP-43和蛋白 (PrP) 的疾病,与病态的超分子组合有关.
- 了解这些蛋白质的中尺度组装动态对于阐明疾病机制至关重要.
研究的目的:
- 开发和验证一个集成全原子 (AA) 和粗粒度 (CG) 建模的多尺度模拟框架,用于研究蛋白质超分子组合.
- 调查模拟参数和离子度对TDP-43和PrP.中等尺度组件的影响.
主要方法:
- 一个多尺度的模拟框架,结合了全原子 (AA) 结构建模,粗粒度 (CG) 马蒂尼3模拟和AA后映射.
- 使用了两个不同的Martini 3 CG参数集,具有不同的非结合相互作用处理 (静电切断,离子缩放).
- 分析了凝结物形态,链动力学 (平均平方位移,扩散性),溶剂可访问性和链间相互作用.
主要成果:
- 该AA-CG-AA框架成功地捕获了TDP-43和PrP.早期超分子凝结的中等尺度特征.
- 不同的CG参数集影响了组件,具有更长的切断点和重新缩放的离子相互作用,促进了更相互连接的,类似网络的组件.
- 观察到蛋白质翻译移动性和离子接触数之间的反向关系,这表明离子协会在凝结中的作用.
结论:
- 综合模拟策略对于在异质蛋白质系统中探测超分子凝结是有效的.
- 结果突出了模拟参数和离子对蛋白质组装的影响,为错误折叠驱动的过程提供了洞察力.
- 支持开发多尺度模拟,用于在疾病背景下研究中观蛋白质组合.
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