Effects of pH on an IDP conformational ensemble explored by molecular dynamics simulation.
Effects of pH on an IDP conformational ensemble explored by molecular dynamics simulation.
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DOI：
10.1016/j.bpc.2021.106552
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发表时间：
2021-04
影响因子：
3.8
通讯作者：
Shen T
中科院分区：
文献类型：
--
作者：
Lindsay RJ;Mansbach RA;Gnanakaran S;Shen T
α-突触核蛋白等内在无序蛋白质的构象集合是其功能和故障的原因。α-突触核蛋白的错误折叠可导致神经退行性疾病，而研究其构象和其他内在无序蛋白质在不同生理条件下的构象对于理解和预防病理至关重要。与折叠良好的多肽相比，IDPs的一个共同特征是低亲水性和高电荷，这使得它们的构象对pH扰动很敏感。我们使用一种分而治之的方案，研究了这一IdP子集中的一个重要成员--α-突触核蛋白，该方案提供了IdP结构集合的增强采样。我们在中性(pH~7)和低pH(pH~3)条件下构建了α-突触核蛋白的构象系综，并将我们的结果与实验SmFRET、小角X射线散射和核磁共振研究中获得的信息进行了比较。具体来说，α-突触核蛋白在低pH条件下被发现处于更紧密的状态，观察到的结构变化与实验结果一致。我们还表征了这些系综之间的构象和动力学差异，并讨论了它们对促进致病原纤维形成的意义。我们发现在低pH条件下，带负电荷的残基的中和导致α-突触核蛋白的C-末端部分紧凑，而内部重组使α-突触核蛋白在两种pH条件下都能保持其总的端到端距离。我们还观察到，在不同的pH下，α-突触核蛋白的三个结构域之间存在不同程度的蛋白内相互作用，并且随着pH的降低，相互作用向更亲水的方向转变。
The conformational ensemble of intrinsically disordered proteins, such as α-synuclein, are responsible for their function and malfunction. Misfolding of α-synuclein can lead to neurodegenerative diseases, and the ability to study their conformations and those of other intrinsically disordered proteins under varying physiological conditions can be crucial to understanding and preventing pathologies. In contrast to well-folded peptides, a consensus feature of IDPs is their low hydropathy and high charge, which makes their conformations sensitive to pH perturbation. We examine a prominent member of this subset of IDPs, α-synuclein, using a divide-and-conquer scheme that provides enhanced sampling of IDP structural ensembles. We constructed conformational ensembles of α-synuclein under neutral (pH ~ 7) and low (pH ~ 3) pH conditions and compared our results with available information obtained from experimental smFRET, SAXS (small-angle X-ray scattering), and NMR studies. Specifically, α-synuclein has been found to in a more compact state at low pH conditions and the structural changes observed are consistent with those from experiments. We also characterize the conformational and dynamic differences between these ensembles and discussed the implication on promoting pathogenic fibril formation. We find that under low pH conditions, neutralization of negatively charged residues leads to compaction of the C-terminal portion of α-synuclein while internal reorganization allows α-synuclein to maintain its overall end-to-end distance under both pH conditions. We also observe different levels of intra-protein interaction between three domains of α-synuclein at varying pH and a shift towards more hydrophilic interactions with decreasing pH.
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影响因子：
4.6
作者：
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作者：
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通讯作者：
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