Multiscale landscape of molecular mechanism of SIRT1 activation by STACs
Multiscale landscape of molecular mechanism of SIRT1 activation by STACs
复制标题
STAC 激活 SIRT1 分子机制的多尺度景观
DOI：
10.1039/c9cp04931b
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发表时间：
2020-01-14
影响因子：
3.3
通讯作者：
Yang, Na
中科院分区：
文献类型：
--
作者：
Liu, Fei;Yang, Na
Sirtuins是一类高度保守的nad依赖性脱乙酰酶，在原核生物和真核生物中参与多种生物过程。SIRT1是表征最好的sirtuin，许多sirtuin激活化合物（STACs）已被报道。然而，STACs激活SIRT1的分子机制仍然存在争议。在这里，我们开发了一个多尺度模拟模型来探索这一机制。通过量化SIRT1- fdl肽-白藜芦醇复合物封闭构象的自由能景观，我们发现活性自由能盆地的势势高度与实验确定的SIRT1被白藜芦醇脱乙酰率波动之间存在正相关。此外，通过监测动力学，我们发现SIRT1-p53-STAC-1复合物的开放构象比封闭结构具有更快的构象变化速度。我们还测定了每种热力学或动力学状态下的结构性质，发现两个潜在的激活因子FdL肽（p53肽底物包括一个AMC荧光基团）结合的稳定性和SIRT1构象的稳定性在一定条件下呈弱相关。这些结果解决了一个有争议的问题，即AMC荧光基团和天然疏水残基在SIRT1激活过程中是否具有相似的作用。最后，我们捕获了过渡的全局景观，包括不稳定和更稳定的状态，并提出了STACs激活SIRT1机制的全局物理景观。
Sirtuins are a family of highly conserved NAD-dependent deacetylase that are involved in multiple biological processes in both prokaryotes and eukaryotes. Many sirtuin-activating compounds (STACs) have been reported for SIRT1, which is the best-characterized sirtuin. However, the molecular mechanism of SIRT1 activation by STACs remains controversial. Here, we developed a multiscale simulation model to explore this mechanism. By quantifying the free energy landscape for the closed conformation of a SIRT1-FdL peptide-resveratrol complex, we found a positive correlation between the barrier height of the active free energy basin and the experimentally determined fluctuations in the rate of SIRT1 deacetylation by resveratrol. In addition, by monitoring dynamics, we found that the open conformation of a SIRT1-p53-STAC-1 complex had a faster rate of conformational change than the closed structure. We also determined the structural properties of each thermodynamic or dynamic state and found that two potential activating factors, the stability of FdL peptide (the p53 peptide substrate including an AMC fluorophore group) binding and the stability of the SIRT1 conformation, were weakly correlated under certain conditions. These results address the controversial question of whether the AMC fluorophore group and native hydrophobic residues have similar roles in the SIRT1 activation process. Finally, we captured the global landscape of the transition, including less stable and more stable states, and proposed a global physical landscape for the mechanism of SIRT1 activation by STACs.