Zhu Wentao, Kong Jianyang, Zhang Jian, Wang Jun, Li Wenfei, Wang Wei
National Laboratory of Solid State Microstructure, and Collaborative Innovation Center of Advanced Microstructures and Department of Physics, Nanjing University, Nanjing 210093, China.
ACS Omega. 2019 Jun 18;4(6):10494-10501. doi: 10.1021/acsomega.9b01217. eCollection 2019 Jun 30.
The wide applications of nanomaterials in industry and our daily life have raised growing concerns on their toxicity to human body. Increasing evidence links the cytotoxicity of nanoparticles to the disruption of cellular signaling pathways. Here, we report a computational study on the mechanisms of the cytotoxicity of carbon nanotubes (CNTs) by investigating the direct impacts of CNTs on the functional motions of calmodulin (CaM), which is one of the most important signaling proteins in a cell, and its signaling function relies on the Ca binding-coupled conformational switching. Computational simulations with a coarse-grained model showed that binding of CNTs modifies the conformational equilibrium of CaM and induces the closed-to-open conformational transition, leading to the loss of its Ca-sensing ability. In addition, the binding of CNTs drastically increases the calcium affinity of CaM, which may disrupt the Ca homeostasis in a cell. These results suggest that the binding of hydrophobic nanotubes not only inhibits the signaling function of CaM as a calcium sensor but also renders CaM to toxic species through sequestering Ca from other competing calcium-binding proteins, suggesting a new physical mechanism of the cytotoxicity of nanoparticles.
纳米材料在工业和我们日常生活中的广泛应用引发了人们对其对人体毒性的日益关注。越来越多的证据将纳米颗粒的细胞毒性与细胞信号通路的破坏联系起来。在此，我们通过研究碳纳米管（CNT）对钙调蛋白（CaM）功能运动的直接影响，报告了一项关于碳纳米管细胞毒性机制的计算研究，钙调蛋白是细胞中最重要的信号蛋白之一，其信号功能依赖于钙结合偶联的构象转换。使用粗粒度模型的计算模拟表明，碳纳米管的结合改变了钙调蛋白的构象平衡并诱导了从关闭到开放的构象转变，导致其钙传感能力丧失。此外，碳纳米管的结合极大地增加了钙调蛋白对钙的亲和力，这可能会破坏细胞内的钙稳态。这些结果表明，疏水性纳米管的结合不仅抑制了钙调蛋白作为钙传感器的信号功能，还通过从其他竞争性钙结合蛋白中螯合钙使钙调蛋白成为有毒物质，这提示了纳米颗粒细胞毒性的一种新物理机制。
