Fei Huaxing, Li Wen, Lu Nan, Liu Qinghuo, Zhang Youyu
Institute of Electromagnetics and Acoustics, Department of Electronic Science, Xiamen University Xiamen 361005 P. R. China
Fujian Engineering Research Center for EDA, Fujian Provincial Key Laboratory of Electromagnetic Wave Science and Detection Technology, Xiamen Key Laboratory of Multiphysics Electronic Information, Institute of Electromagnetics and Acoustics, Xiamen University Xiamen 361005 P. R. China
RSC Adv. 2023 May 31;13(24):16311-16320. doi: 10.1039/d2ra07552k. eCollection 2023 May 30.
Musk xylene (MX), a kind of personal care product, has become a new type of environmental contaminant in recent years. Long-term exposure to MX is associated with a variety of cancers, but the mechanism is still unclear. Meanwhile, our previous research showed that MX exposure could lead to malignant transformation of human liver cells L02 and up-regulation of multi genes which are involved in the MAPK signaling pathway, such as the epidermal growth factor receptor (EGFR). These findings indicated that the MAPK signaling pathway might be involved in the malignant transformation caused by MX, but the mechanism is also unclear. In this study, the underlying interaction mechanisms between EGFR and MX were investigated using molecular dynamics (MD) simulation. Results revealed that MX bound to the ECD of EGFR in four binding sites, which was mainly driven by van der Waals and nonpolar interactions, and the affinity of MX toward ECD was sIII > sI > sII > sIV. Further analysis through MD simulation found that s III, the site with the strongest binding, was coincidentally located at the binding area of EGF, which is the natural ligand of EGFR. Therefore, we speculated that MX may activate the MAPK signaling pathway by binding to EGFR in a similar way to EGF, and finally lead to tumorigenesis. In addition, the MM/PBSA method could also be utilized to calculate the hot residues in each binding site. The prediction of hot residues would provide some theoretical guidance for further study of the carcinogenesis mechanisms of MX both in MD simulation and experimental research.
麝香二甲苯（MX）是一种个人护理产品，近年来已成为一种新型环境污染物。长期接触MX与多种癌症有关，但其机制仍不清楚。同时，我们之前的研究表明，MX暴露可导致人肝细胞L02发生恶性转化，并上调参与丝裂原活化蛋白激酶（MAPK）信号通路的多个基因，如表皮生长因子受体（EGFR）。这些发现表明，MAPK信号通路可能参与了MX引起的恶性转化，但其机制也不清楚。在本研究中，利用分子动力学（MD）模拟研究了EGFR与MX之间潜在的相互作用机制。结果显示，MX在四个结合位点与EGFR的细胞外结构域（ECD）结合，主要由范德华力和非极性相互作用驱动，MX对ECD的亲和力为sIII > sI > sII > sIV。通过MD模拟进一步分析发现，结合最强的位点s III恰好位于EGFR天然配体表皮生长因子（EGF）的结合区域。因此，我们推测MX可能通过与EGF类似的方式与EGFR结合来激活MAPK信号通路，最终导致肿瘤发生。此外，MM/PBSA方法也可用于计算每个结合位点的热点残基。热点残基的预测将为进一步研究MX在MD模拟和实验研究中的致癌机制提供一些理论指导。
