Comparative QM/MM Molecular Dynamics and Umbrella Sampling Simulations: Interaction of the Zinc-Bound Intermediate Gem-Diolate Trapoxin A Inhibitor and Acetyl-l-lysine Substrate with Histone Deacetylase 8.
Comparative QM/MM Molecular Dynamics and Umbrella Sampling Simulations: Interaction of the Zinc-Bound Intermediate Gem-Diolate Trapoxin A Inhibitor and Acetyl-l-lysine Substrate with Histone Deacetylase 8.
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比较 QM/MM 分子动力学和伞式采样模拟：锌结合中间 Gem-Diolate Trapoxin A 抑制剂和乙酰基-L-赖氨酸底物与组蛋白脱乙酰酶 8 的相互作用。
DOI：
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发表时间：
2021
影响因子：
3.3
通讯作者：
Needa Zalloum
中科院分区：
文献类型：
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作者：
Waleed A. Zalloum;Needa Zalloum
靶向遗传物质而不破坏是开发安全抗癌药物的优先事项。组蛋白去乙酰化酶8（HDAC 8）是一种与染色质相关的酶，负责乙酰化赖氨酸的翻译后去乙酰化。在这项研究中，HDAC 8共结晶的中间状态四肽Trapoxin A（TA）抑制剂和全酶被用来找到他们的构象合奏。此外，共结晶的中间体Gem-diolate TA被用来找到最佳的相互作用与活性中心的残基通过常规的分子动力学（MD）模拟和QM/MM伞采样。最后，乙酰基-L-赖氨酸底物的中间状态通过QM/MM转向MD进行了探索，并与抑制剂的中间状态的结合进行了比较。这项研究表明，HDAC 8是灵活的，并存在于其全酶状态的构象系综。中间态TA的结合稳定了其构象。根据相应的能量分布，确定了Gem-diolate TA（中间态）和乙酰基-1-赖氨酸（中间态）结构与HDAC 8活性位点的最佳结合。这些模型的使用将有助于设计用于癌症治疗的潜在可逆的，有效的和选择性的HDAC 8抑制剂。
Targeting the genetic material without destruction is a priority to develop safe anticancer drugs. Histone deacetylase 8 (HDAC8), which is proved to be involved in carcinogenesis, is an enzyme associated with the chromatin for post-translational deacetylation of acetylated lysine. In this study, HDAC8 co-crystallized with the intermediate state tetrapeptide Trapoxin A (TA) inhibitor and the holoenzyme are utilized to find their conformational ensembles. Furthermore, the co-crystallized intermediate gem-diolate TA was used to find optimum interactions with the active site residues by conventional molecular dynamics (MD) simulation and QM/MM umbrella sampling. Finally, the intermediate state of the acetyl-l-lysine substrate was explored by QM/MM steered MD and compared to the binding of the intermediate state of the inhibitor. This research showed that HDAC8 is flexible and exists in conformational ensembles in its holoenzyme state. Binding of the intermediate state TA stabilizes its conformation. The optimum binding to the active site of HDAC8 for structures of gem-diolate TA (intermediate state) and acetyl-l-lysine (intermediate state) was determined according to the corresponding energy profiles. The use of these models will aid in the design of potentially reversible, potent, and selective inhibitors of HDAC8 for cancer treatment.
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