In Silico Evaluation of Variable pH on the Binding of Epidermal Growth Factor Receptor Ectodomain to its Ligand Through Molecular Dynamics Simulation in Tumors.

Many aggressive and metastatic cancer cell types show Warburg Effect; therefore, it is a possible adaptation helping cancer cells to rapidly divide and utilize the glycolytic intermediates for biosynthesis of ribose sugars (for nucleotide biosynthesis), fatty acid synthesis (lipids for membrane synthesis), NADPH (cellular currency for reductive biosynthesis) and lactate. This in due course results in decrease of extracellular pH, leading to acidic tumor micro-environment. EGFR is a crucial cell surface signaling receptor implicated in cancer cell survival and progression. This warrants studying the effect of the acidic micro-environmental conditions on the binding of the EGFR cell surface receptor to one of its natural extracellular ligand EGF. We exploited in silico approaches: molecular dynamics simulation at variable pH and MM-GBSA free energy of binding calculation method to evaluate the effect of this change in microenvironmental pH. Through the present study it is reported that at pH 6.6 the EGFR binds to EGF with decreased free energy of binding as compared to pH 7.2.