Molecular dynamic simulation reveals the molecular interactions of epidermal growth factor receptor with musk xylene are involved in the carcinogenicity

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.