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模拟导向的符合性空间探索,以评估一个 ribozyme 的反应性构造

Sélène Forget¹, Marie Juillé^1,2, Elise Duboué-Dijon²

¹PASTEUR, Département de chimie, École Normale Supérieure, PSL University, Sorbonne Université, CNRS, 24 rue Lhomond, 75005 Paris, France.

Journal of chemical theory and computation

|July 3, 2024

概括

了解 ribozyme 反应需要探索关键的反应前状态. 这项研究表明,最稳定的构造,而不是通常假定的反应性构造,可能会驱动毛 ribozyme 自分裂.

科学领域:

生物化学生物化学
计算生物学计算生物学
生命的起源研究生命的起源研究

背景情况:

自剪接的 ribozymes (RNA 酶) 对于病毒 RNA 处理和潜在的早期生命至关重要.
了解它们的催化机制是关键,但对短寿命反应中间体的实验性表征是困难的.
分子模拟提供了一种强大的方法来研究这些复杂的生物化学反应.

研究的目的:

为了研究头发针 ribozyme 在自我切割之前的构造景观.
为了确定催化最相关的反应物状态构造.
了解模拟 ribozyme 反应的挑战,包括力场准确性和 conformational 采样.

主要方法:

用分子动力学 (MD) 模拟来研究毛针 ribozyme.
哈密尔顿复制品交换模拟用于广泛的构造相位空间探索.
分析的重点在于在自我裂变之前的结合状态下表征构造盆地.

主要成果:

通常假设的"反应性"形状是转移稳定且人口稀少的.
确定了一种热力学稳定的构造,不直接涉及化过程中的 ribozyme 残留物.
多重力场,有足够的抽样,始终支持这些发现.

结论:

确定正确的反应前形状与确定反应动力学和热力学一样重要.
这些发现挑战了以前关于毛利波酶催化机制的假设.
准确的构造性采样对于可靠的分子模拟里波酶活性至关重要.

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