Abstract
Epidermal growth factor (EGF) plays important roles in multiple biological processes, such as the regulation of cell growth, proliferation, and differentiation. EGF exerts their pharmacologic effects via receptor-mediated mechanism associated with high affinity to epidermal growth factor receptor (EGFR) on the cell surface. Overexpression of EGFR has been reported and implicated in the pathogenesis of many human cancers. The current study addresses the effects of mutations on binding properties of EGF to EGFR. Two mutant structures with three point mutations of conserved residues, Ile23, Arg41 and Leu47, which have been found to be important for the receptor binding, were built using homology modeling. The “wild type” (WT) and the mutant structures, after structural validations, were subjected to molecular dynamics simulations (MDSs). The primary aim of MDS was to investigate the possible impact of mutations on the protein structure and function. Analysis of root mean square deviation (RMSD), other time dependent structural properties and their averages provided some insights into the possible structural characteristics of the mutant and the WT forms of the EGF. RMSD analysis showed that WT EGF was more stable than the mutant structures. The docking analysis revealed that the binding energy of mutant EGFs to EGFR is lower than WT. Combination of the used computational approaches provides a way in understanding the impact of deleterious mutations in altering the EGF and EGFR interactions.
Acknowledgments
The authors gratefully acknowledge Vice Chancellor for Research and Technology, Kermanshah University of Medical Sciences.