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通过310K的分子动力学模拟,达到冷-EM重建的全部潜力:举例来说,阿克丝

Sahithya Sridharan Iyer¹, Kristina M Herman¹, Tamsuk Paul¹

¹Department of Chemistry, Chicago Center for Theoretical Chemistry, Institute for Biophysical Dynamics, and James Franck Institute, The University of Chicago, Chicago, IL 60637.

Proceedings of the National Academy of Sciences of the United States of America

|November 25, 2025

概括

电子显微镜 (cryo-EM) 可能无法捕捉生理蛋白质状态. 分子动力学模拟显示,在310K时,actin线丝采用更高度,扭曲的形状,影响ATP水解和子单元协会.

科学领域:

结构生物学是结构生物学.
生物物理学的生物物理.
计算生物学是一种计算生物学.

背景情况:

低温电子显微镜 (cryo-EM) 提供了像actin丝状的蛋白质复合体的高分辨率结构.
在冷EM中快速结可能会捕获非生理性构造,限制对动态过程的理解.
全原子分子动力学 (MD) 模拟可以在生理温度下探索蛋白质的行为.

研究的目的:

用MD模拟研究在生理温度 (310K) 上的行为丝的构造动力学.
将模拟形状与冷电磁结构进行比较,并了解温度依赖的结构差异.
阐明作用因子线组合,ATP水解以及与其他蛋白质相互作用的基础分子机制.

主要方法:

全原子分子动力学模拟是从actin纤维的冷EM重建开始的.
对310 K的形状波动,子单元方向和活跃站点配置的分析.
模拟的丝动态与现有的冷EM数据和丝单体模拟的比较.

主要成果:

在310K,ADP-actin线丝与冷-EM结构相比,具有扭曲的子单元和改变的螺旋参数,呈现出更高的状态.
在ATP水解活性位点中的关键残留物和催化水在310K时很少采用最佳配置,这解释了缓慢的水解.
ADP-Pi-actin细丝显示了酸盐释放的开放后门,并且发生了cofilin和phalloidin的结合点的短暂开放.
尖端的子单元结合受到扭曲的形状的阻碍,而尖端的子单元则表现出动态的横向相互作用.

结论:

化EM结构可能代表了由于结而导致的酸纤维的平坦,非生理状态.
在生理温度下进行的MD模拟揭示了动态形状组合,这对于理解丝功能至关重要.
温度依赖的形状变化显著影响ATP水解速率,蛋白质-蛋白质相互作用和丝状动态,突出了在结构生物学中对MD模拟的需求.

关键词:

通过ATP的水解.亚丁丝是一种亚丁丝.低温电磁波冷却器 (Cryo-EM) 是一个非常好的方法.分子动力学分子动力学酸盐解离的解离方式

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