EGF Super-Agonists Induce Structural Stabilization and Domain-Specific Binding in EGFR: A Computational Analysis

Abstract

Background: The interaction between epidermal growth factor (EGF) and its receptor (EGFR) is a critical process in wound healing, owing to their role in initiating epidermal and dermal regeneration. EGF-based therapies enhance wound healing, and engineered EGF mutants with increased EGFR binding are designed to further improve this effect. Objectives: This study aimed to utilize molecular dynamics simulations (MDS) to comprehensively analyze the interactions between EGF mutants and EGFR, providing mechanistic insights that could inform the design of novel therapeutics for wound healing and regenerative medicine. Methods: Molecular dynamics simulations were performed to investigate the key molecular interactions and binding dynamics between wild-type EGF (WT-EGF) and two engineered EGF mutants (m28-EGF and m123-EGF) in complex with EGFR. Comparative analyses of structural stability, binding affinity, and interaction energy were conducted to elucidate the molecular basis of enhanced receptor activation by these mutants. Results: Molecular dynamics simulation results indicated that the introduced mutations rendered the EGF mutants less flexible, allowing them to adopt more compact and stable structures. Accordingly, the mutations in m28-EGF and m123-EGF significantly affected their binding affinity to EGFR, with m28-EGF exhibiting a preference for domain I and m123-EGF showing a preference for domain III of EGFR. Additionally, analysis of the EGFR dimerization domain revealed that the EGFR chains in the mutant complexes demonstrated an increased capacity to form hydrogen bonds and hydrophobic interactions compared to the wild type. Notably, the calculated interaction energies in the m123-EGF/EGFR complex were higher than those in other complexes, indicating a stronger binding affinity. These findings underscore the pivotal contribution of domain II to EGFR dimer stability and its essential role in maintaining the EGF–EGFR interaction. Conclusions: These results suggest that EGF super-agonists hold significant promise in regenerative medicine and that targeting ligand–receptor interactions can facilitate therapeutic development to modulate EGFR signaling. Understanding how ligands induce conformational changes in EGFR could lead to new treatments and personalized medicine for EGFR-related diseases, although the diverse effects of different ligands warrant further investigation.