通过广泛的分子动力学模拟分析 BAX 上的结合位点和 BAX 激活剂的作用机制,Journal of Chemical Information and Modeling

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通过广泛的分子动力学模拟分析 BAX 上的结合位点和 BAX 激活剂的作用机制
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2021-05-28 , DOI: 10.1021/acs.jcim.0c01420
Guoqin Feng _{1,

2} , Xiangying Zhang ₁ , Yan Li ₁ , Renxiao Wang _{1,

2,

3}

Affiliation

BAX 蛋白是 Bcl-2 家族的促凋亡成员，它通过引起线粒体外膜的透化作用来触发细胞凋亡。然而，BAX 的激活机制远未被理解。尽管文献中报道了一些小分子 BAX 激活剂，但它们与 BAX 复合的晶体结构尚未得到解析。到目前为止，它们的结合模式最多只能通过简单的分子对接来模拟。缺乏对 BAX 激活机制的深入了解阻碍了更有效的 BAX 激活剂的开发。在这项工作中，我们采用共溶剂分子动力学模拟来检测 BAX 表面的潜在结合位点，并进行了长时间的分子动力学模拟（总共 50 μs）来推导三种 BAX 激活剂的可能结合模式（即，BAM7、BTC-8 和 BTSA1) 在文献中有报道。我们的结果表明触发器、S184 和 vMIA 站点是全长 BAX 结构上的三个主要绑定站点。此外，在α9截短的BAX结构上清楚地检测到典型的疏水沟，这与相关实验研究的结果一致。有趣的是，观察到溶剂探针与触发底袋的结合比 PPI 触发位点更稳定。在五个平行作业中，每个激活剂都经过了从三个主要结合位点开始的无偏分子动力学模拟。我们的 MD 结果表明，所有三种激活剂都倾向于停留在具有有利 MM-GB/SA 结合能的触发位点。BAM7 和 BTSA1 可以进入触发器底袋，从而增强 α1−α2 环的运动，这可能是 BAX 激活早期的关键因素。我们的分子建模结果可能为设计智能生物实验以进一步探索 BAX 激活和指导基于结构的努力发现更有效的 BAX 激活剂提供有用的指导。

"点击查看英文标题和摘要"

Analysis of the Binding Sites on BAX and the Mechanism of BAX Activators through Extensive Molecular Dynamics Simulations

The BAX protein is a pro-apoptotic member of the Bcl-2 family, which triggers apoptosis by causing permeabilization of the mitochondrial outer membrane. However, the activation mechanism of BAX is far from being understood. Although a few small-molecule BAX activators have been reported in the literature, their crystal structures in complex with BAX have not been resolved. So far, their binding modes were modeled at most by simple molecular docking efforts. Lack of an in-depth understanding of the activation mechanism of BAX hinders the development of more effective BAX activators. In this work, we employed cosolvent molecular dynamics simulation to detect the potential binding sites on the surface of BAX and performed a long-time molecular dynamics simulation (50 μs in total) to derive the possible binding modes of three BAX activators (i.e., BAM7, BTC-8, and BTSA1) reported in the literature. Our results indicate that the trigger, S184, and vMIA sites are the three major binding sites on the full-length BAX structure. Moreover, the canonical hydrophobic groove is clearly detected on the α9-truncated BAX structure, which is consistent with the outcomes of relevant experimental studies. Interestingly, it is observed that solvent probes bind to the trigger bottom pocket more stably than the PPI trigger site. Each activator was subjected to unbiased molecular dynamics simulations started at the three major binding sites in five parallel jobs. Our MD results indicate that all three activators tend to stay at the trigger site with favorable MM-GB/SA binding energies. BAM7 and BTSA1 can enter the trigger bottom pocket and thereby enhance the movement of the α1−α2 loop, which may be a key factor at the early stage of BAX activation. Our molecular modeling results may provide useful guidance for designing smart biological experiments to further explore BAX activation and directing structure-based efforts toward discovering more effective BAX activators.

更新日期：2021-05-28

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