来自原子分子动力学模拟的种子Aβ40-纤维生长动力学:锁定步骤中的动力捕获和减少水流动性
Nadine Schwierz1, Christina V Frost2, Phillip L Geissler1
1Chemistry Department, University of California , Berkeley, California 94720, United States.
Journal of the American Chemical Society
|December 24, 2015
概括
阿尔茨海默病的粉样β (Aβ) 纤维的生长是由溶剂而不是直接的相互作用驱动的. 分子动力学模拟显示了"对接/锁定"机制,最初的对接是快速的,其次是较慢的构造变化.
科学领域:
- 生物物理
- 神经科学
- 计算化学
背景情况:
- 丝状β-粉样 (Aβ) 聚合物是阿尔茨海默病病理学的核心.
- Aβ纤维细胞生长的分子机制尚未完全理解,这对模拟研究构成了挑战.
研究的目的:
- 通过全原子分子动力学模拟,阐明Aβ9-40纤维细胞生长的分子路径和动力学.
- 确定驱动力和控制纤维延长和碎片结合的关键步骤.
主要方法:
- 在水中进行广泛的全原子分子动力学模拟.
- 从位置依赖的扩散配置文件计算自由能量配置文件和动力信息.
- 通过单体和较大的片段分析Aβ9-40纤维的延长.
主要成果:
- 溶剂,而不是直接的相互作用,是Aβ纤维组合的主要驱动因素.
- 一个"对接/锁定"机制控制了生长动力学,对接比锁定要快得多.
- 过渡的非原生键有助于快速对接,而较慢的锁定则涉及动态捕获的构造.
结论:
- 由于相互竞争的-和溶解相互作用,纤维的生长在能量方面受到不利影响.
- 在纤维细胞生长过程中,水动力学和集体运动对于形成干结接口至关重要.
- 减少水分流动性显著减缓了纤维的整体生长速度.
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