title: Critical effects on binding of epidermal growth factor produced by amino acid substitutions.
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.
authors.affiliation: a Medical Biology Research Center, Kermanshah University of Medical Sciences , Kermanshah , Iran.
authors.forename: Masomeh
authors.initials: M
authors.lastname: Mehrabi
authors.affiliation: b Nano Drug Delivery Research Center, Kermanshah University of Medical Sciences , Kermanshah , Iran.
authors.forename: Reza
authors.initials: R
authors.lastname: Khodarahmi
authors.affiliation: c Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Kermanshah University of Medical Sciences , Kermanshah , Iran.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Shahlaei
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000596:Amino Acids; D001665:Binding Sites; D004815:Epidermal Growth Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D004815:Epidermal Growth Factor; D066246:ErbB Receptors
keywords: docking; epidermal growth factor; molecular dynamics simulation; molecular modeling; point mutation