使用原子模拟,阐明底层全长FUS形态转换的分子相互作用网络及其相位分离
Shuo-Lin Weng1, Priyesh Mohanty2, Jeetain Mittal1,2,3
1Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States.
The journal of physical chemistry. B
|August 22, 2025
概括
全原子分子动力学模拟揭示了FUS蛋白相互作用如何驱动液-液相分离 (LLPS). 强力场的选择影响了模拟的准确性,Amber ff99SBws-STQ显示了对折叠域的稳定性.
科学领域:
- 生物物理
- 分子生物学
- 结构生物学
背景情况:
- 化在肉瘤 (FUS) 是一种通过液相分离 (LLPS) 调节基因表达和DNA修复的关键蛋白质.
- 由于其在体外溶解度较低,因此很难在原子层面上理解FUS LLPS.
- 全长度 (FL) FUS的形态动态和相互作用对其功能至关重要.
研究的目的:
- 通过全原子分子动力学 (AA-MD) 模拟来研究全长FUS在稀释和凝结阶段的结构动力学和相互作用.
- 为了比较两个现代分子动力学力场 (FFs) 的性能:珀 ff03ws 和 ff99SBws-STQ.
- 阐明FUS LLPS中折叠域和内在无序区域 (IDR) 的作用.
主要方法:
- 全原子分子动力学 (AA-MD) 模拟全长FUS.
- 珀 ff03ws 和 ff99SBws-STQ 的力场比较.
- 微秒时间尺度模拟FUS冷凝物.
主要成果:
- 这两种FF均表现出相似的分子内相互作用,其中IDR占主导地位.
- 折叠域稳定性显著影响了链条尺寸,导致与实验数据的差异.
- 使用ZAFF参数的珀 ff99SBws-STQ提高了折叠域稳定性和链维度估计.
- FUS冷凝模拟显示了与稀释相构成相关的广泛的静电相互作用.
结论:
- 强力场的选择对于精确模拟FUS和LLPS的形态动态至关重要.
- 稳定的折叠域和IDR相互作用之间的相互作用决定了FUS的构造和相位分离.
- AA-MD模拟为FUS LLPS的分子机制提供了宝贵的见解.
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