在从固态转化为水溶液时,SARS-CoV-2 主蛋白酶的水触发的,不可逆转的构造变化
Narjes Ansari1, Valerio Rizzi1, Paolo Carloni2,3
1Italian Institute of Technology, Via E. Melen 83, 16152 Genova, Italy.
Journal of the American Chemical Society
|August 16, 2021
概括
SARS-CoV-2 主蛋白酶最初是一个二元体,在溶液中打破对称性,形成不同的亚单元构造. 在这种不可逆转的转变中, 水分子是关键触发因素,
科学领域:
- 生物化学
- 分子生物学
- 计算化学
背景情况:
- SARS-CoV-2 主蛋白酶 (Mpro) 是一种关键的病毒酶,也是抗病毒药物开发的目标.
- Mpro作为同位素的功能,但其溶液中的结构动力学尚未完全理解.
研究的目的:
- 研究SARS-CoV-2 Mpro在从固态转化为水溶液时的形状变化.
- 确定水分子在这些构造转换中的作用.
- 确定观察到的对称性破坏事件的可逆性.
主要方法:
- 对SARS-CoV-2 Mpro的0.1毫秒分子动力学 (MD) 模拟的分析.
- 增强采样模拟以探索构造性景观.
- 机器学习方法分析模拟数据并确定关键因素.
主要成果:
- 在从固体转化为水溶液时,SARS-CoV-2 Mpro 很容易发生对称性破坏事件.
- 小单元采用不同的结合口袋形状,受特定的水分子相互作用的影响.
- 过渡到不对称状态被发现基本上是不可逆转的.
结论:
- 水分子在引发SARS-CoV-2 Mpro的对称性破坏转变方面发挥着至关重要的,以前未知的作用.
- 观察到的不对称性和水分子的作用对理解Mpro功能和设计向抑制剂具有重要意义.
- 过渡的不可逆转性突显了生理环境中的Mpro动态的复杂性.
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