National Laboratory of Solid State Microstructure, Collaborative Innovation Center of Advanced Microstructures, and School of Physics , Nanjing University , Nanjing 210093 , P.R. China.
J Phys Chem B. 2019 Jun 27;123(25):5216-5228. doi: 10.1021/acs.jpcb.9b02457. Epub 2019 Jun 18.
Copper ions are important cofactors of many metalloproteins. The binding dynamics of proteins to the copper ion is important for biological functions but is less understood at the microscopic level. What are the key factors determining the recognition and the stabilization of the copper ion during the binding? Our work investigates the binding dynamics of the copper ion with a simple system (the N-terminus of PrP) using simulation methods. To precisely characterize the protein?ion interaction, we build up an effective copper?peptide force field based on quantum chemistry calculations. In our model, the effects of charge transfer, protonation/deprotonation, and induced polarization are considered. With this force field, we successfully characterize the local structures and the complex interactions of the octapeptide around the copper ion. Furthermore, using an enhanced sampling method, the binding/unbinding processes of the copper ion with the octapeptide are simulated. Free-energy landscapes are generated in consequence, and multiple binding pathways are characterized. It is observed that various native ligands contribute differently to the binding processes. Some residues are related to the capture of the ion (behaving like ?arm?s), and some others contribute to the stabilization of the coordination structure (acting like ?core?s). These different interactions induce various pathways. Besides, a nonnative binding ligand is determined, and it has essential contributions and modulations to the binding pathways. With all these results, the picture of copper?octapeptide binding is outlined. These features are believed to happen in many ion?peptide interactions, such as the cooperative stabilization between the coordinations with neighboring backbone nitrogens and an auxiliary intermediate coordination with the neighboring oxygen from the N-terminal direction. We believe that our studies are valuable to understand the complicated ion?peptide binding processes.
铜离子是许多金属蛋白的重要辅因子。蛋白质与铜离子的结合动力学对于生物功能至关重要，但在微观水平上的了解较少。在结合过程中，决定铜离子识别和稳定的关键因素是什么？我们的工作使用模拟方法研究了简单体系（PrP 的 N 端）中铜离子的结合动力学。为了精确描述蛋白质-离子相互作用，我们基于量子化学计算构建了一个有效的铜-肽力场。在我们的模型中，考虑了电荷转移、质子化/去质子化和诱导极化的影响。利用这个力场，我们成功地描述了八肽周围局部结构和复杂相互作用。此外，我们使用增强采样方法模拟了铜离子与八肽的结合/解吸过程。因此，生成了自由能景观，并对多种结合途径进行了表征。结果观察到，各种天然配体对结合过程的贡献不同。一些残基与离子的捕获有关（表现为“臂”），而另一些残基则有助于配位结构的稳定（起“核心”作用）。这些不同的相互作用诱导了不同的途径。此外，还确定了一个非天然结合配体，它对结合途径有重要的贡献和调节作用。有了这些结果，我们勾勒出了铜-八肽结合的画面。这些特征被认为发生在许多离子-肽相互作用中，例如配位与相邻骨架氮之间的协同稳定以及来自 N 端方向的相邻氧的辅助中间配位。我们相信，我们的研究对于理解复杂的离子-肽结合过程是有价值的。
