Docking and molecular dynamics simulation study of EGFR1 with EGF-like peptides to understand molecular interactions

Abstract

Epidermal growth factor receptors (EGFRs) are oncogenes, which regulate the expression of genes in various pathways, allowing cells to grow and divide. EGF-like growth factors bind to the extracellular region of EGFR causing EGFR dimerization (homo/hetero) and activation of the intrinsic protein kinase activity of the EGFR. The binding potentials of different growth factors vary from nanomolar to micromolar, because of changes in conformational state of EGFR1 bound to different growth factors. Our aim is to predict the key amino acid residues that are vital to activation of EGFR1, stimulating subsequent conformational changes in the extracellular region and its dimerization. Protein–peptide docking was performed using HADDOCK and molecular dynamics simulations of complexes were done using Gromacs. Dynamic domain movement studies were performed to understand the conformational changes in the domains of EGFR1. We predicted epidermal growth factor, transforming growth factor-α, heparin-binding epidermal growth factor, and betacellulin would show better interactions than epiregulin and neuregulin with EGFR1. The study identifies the altered behavior of crucial EGFR1 residues Cys305, Gly307, Arg310, and Val312, which is suggestive of their probable role in dimerization of EGFRs and activation of the tyrosine kinase domain, which is associated with cancer.