Metastable States in the Hinge-Bending Landscape of an Enzyme in an Atomistic Cytoplasm Simulation
Metastable States in the Hinge-Bending Landscape of an Enzyme in an Atomistic Cytoplasm Simulation
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DOI：
10.1021/acs.jpclett.3c03134
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发表时间：
2024-01-22
影响因子：
5.7
通讯作者：
Gruebele，Martin
中科院分区：
文献类型：
--
作者：
Samuel Russell，Premila P.;Maytin，Andrew K.;Gruebele，Martin
许多酶经历主要的构象变化以在细胞中发挥功能，特别是当它们结合到一个以上的底物时。我们量化了人类磷酸甘油酸激酶（PGK）在人类细胞质中的大幅度铰链弯曲景观。大约70 μs的全原子模拟，在粗粒化，揭示了三个亚稳态的PGK与不同的铰链角分布和额外的子状态。“开放”州的人口比“半开放”或“封闭”州的人口多。除了景观内的自由能和势垒外，我们还表征了平均过渡态通过时间为10.3 μs以及可逆的底物和产物结合。人PGK在稀溶液模拟显示直接从开放到封闭状态的过渡，与以前的SAXS实验一致，表明细胞样模型环境促进了人PGK半开放状态的稳定性。酵母PGK还在细胞质模型中采样了三种亚稳态，其中封闭状态在我们的模拟中受到青睐。
Many enzymes undergo major conformational changes to function in cells, particularly when they bind to more than one substrate. We quantify the large-amplitude hinge-bending landscape of human phosphoglycerate kinase (PGK) in a human cytoplasm. Approximately 70 μs of all-atom simulations, upon coarse graining, reveal three metastable states of PGK with different hinge angle distributions and additional substates. The “open” state was more populated than the “semi-open” or “closed” states. In addition to free energies and barriers within the landscape, we characterized the average transition state passage time of ≈0.3 μs and reversible substrate and product binding. Human PGK in a dilute solution simulation shows a transition directly from the open to closed states, in agreement with previous SAXS experiments, suggesting that the cell-like model environment promotes stability of the human PGK semi-open state. Yeast PGK also sampled three metastable states within the cytoplasm model, with the closed state favored in our simulation.