Molecular dynamic simulation reveals the molecular interactions of epidermal growth factor receptor with musk xylene...

Area of Science:

• Environmental toxicology
• Molecular biology
• Computational chemistry

Background:

• Musk xylene (MX) is an emerging environmental contaminant found in personal care products.
• Long-term MX exposure is linked to various cancers, but the underlying mechanisms remain unclear.
• Previous studies indicated MX exposure induces malignant liver cell transformation and upregulates MAPK pathway genes, including EGFR.

Purpose of the Study:

• To investigate the interaction mechanisms between Musk xylene (MX) and the epidermal growth factor receptor (EGFR) using molecular dynamics (MD) simulations.
• To elucidate how MX binding to EGFR might contribute to tumorigenesis.
• To identify potential binding sites and interactions for further experimental validation.

Main Methods:

• Molecular dynamics (MD) simulations were employed to model the interaction between MX and the extracellular domain (ECD) of EGFR.
• Binding affinities and interaction types (van der Waals, nonpolar) were analyzed.
• MM/PBSA methods were used to predict hot residues at the binding sites.

Main Results:

• MX was found to bind to four distinct sites on the EGFR ECD, with the strongest affinity at site sIII.
• The primary binding forces were van der Waals and nonpolar interactions.
• Site sIII, where MX binds most strongly, overlaps with the binding area of EGF, EGFR's natural ligand.

Conclusions:

• MX may activate the MAPK signaling pathway by binding to EGFR in a manner similar to its natural ligand, EGF.
• This interaction mechanism provides a potential explanation for MX-induced liver cell malignant transformation and tumorigenesis.
• Identifying hot residues offers theoretical guidance for future experimental studies on MX carcinogenesis.