Multimodal Structural Distribution of the p53 C-Terminal Domain upon Binding to S100B via a Generalized Ensemble Method: From Disorder to Extradisorder
Multimodal Structural Distribution of the p53 C-Terminal Domain upon Binding to S100B via a Generalized Ensemble Method: From Disorder to Extradisorder
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DOI：
10.1021/acs.jctc.8b01042
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发表时间：
2019-04-01
影响因子：
5.5
通讯作者：
Higo, Junichi
中科院分区：
文献类型：
--
作者：
Iida, Shinji;Kawabata, Takeshi;Higo, Junichi
蛋白质的内在无序区（IDRs）在识别伴侣分子时采用灵活的结合方式。此外，人们认识到idr与伴侣分子的结合伴随着折叠，在复合物的形成中经常允许各种结合构象。在这项研究中，我们研究了p53 c末端结构域（CTDO）的一个片段，它与它的一个伙伴分子S100B相互作用，作为一个代表性的IDR。虽然CTDf与S100B配合物的三维结构已经有报道，但具体的相互作用仍然存在争议。为了澄清这些相互作用，我们进行了广义系综分子动力学（MD）模拟（虚拟系统耦合多规范MD，称为V-McMD），该模拟能够实现比传统MD提供的更有效的构象采样。这些模拟为我们的系统生成了包括CTDf和S100B在内的多模态结构分布，表明CTDf在与S100B结合后形成了各种复杂结构。我们证实，我们的结果是一致的化学位移扰动和核Overhauser效应，在以前的研究中观察到的。此外，我们还计算了CTDf在束缚态和孤立态（自由）下的构象熵。这些CTDf熵的比较表明，无序CTDf与S100B结合后，构象多样性进一步增加。这种通过结合获得的熵增益可能包含idr复合物形成的一个重要特征。
Intrinsically disordered regions (IDRs) of a protein employ a flexible binding manner when recognizing a partner molecule. Moreover, it is recognized that binding of IDRs to a partner molecule is accompanied by folding, with a variety of bound conformations often being allowed in formation of the complex. In this study, we investigated a fragment of the disordered p53 C-terminal domain (CTDO that interacts with one of its partner molecules, S100B, as a representative IDR. Although the 3D structure of CTDf in complex with S100B has been previously reported, the specific interactions remained controversial. To clarify these interactions, we performed generalized ensemble molecular dynamics (MD) simulations (virtual-system coupled multi- canonical MD, termed V-McMD), which enable effective conformational sampling beyond that provided by conventional MD. These simulations generated a multimodal structural distribution for our system including CTDf and S100B, indicating that CTDf forms a variety of complex structures upon binding to S100B. We confirmed that our results are consistent with chemical shift perturbations and nuclear Overhauser effects that were observed in previous studies. Furthermore, we calculated the conformational entropy of CTDf in bound and isolated (free) states. Comparison of these CTDf entropies indicated that the disordered CTDf shows further increase in conformational diversity upon binding to S100B. Such entropy gain by binding may comprise an important feature of complex formation for IDRs.