New Insights to Hydrogen Bonds to Provide Stability in the EGFR Related to Non-small Cell Lung Cancer

Abstract

Lung cancer is the most common cancer in the world, but it is one of the most preventable. Non-small cell lung cancer accounts for approximately 85% of all lung cancers. Epidermal growth factor receptor or EGFR is the class of high-affinity cell surface receptors which are essential in regulating biological processes including cell differentiation, cell survival or death, and cellular metabolism. An amino acid substitution at the 858th position of EGFR, from a Leucine(L) to an Arginine(R) causes L858R mutation within exon 21, which encodes part of the kinase domain and drives to NSCLC. For over 60% of EGFR-muted NSCLC, another mutation T790M can cause drug resistance to erlotinib or gefitinib. In our research work, we considered three structures of EGFR, wild-type, with L858R mutation and with L858R/T790M drug-resistance mutation. The number of hydrogen bond decreases when the EGFR becomes mutated and it reduces even more in its drug-resistance structure. We perform 200 frames of molecular dynamics (MD) simulation to analyze the behavioral changes in hydrogen bonds for all three structures. Since the hydrogen bonds contribute to the conformational stability of the protein and molecular recognition, the knowledge, and results achieved from this study lead to useful insight into the mechanism of NSCLC drug resistance.