Functional roles of magnesium binding to extracellular signal-regulated kinase 2 explored by molecular dynamics simulations and principal component analysis.

Molecular dynamics (MD) simulations coupled with principal component (PC) analysis were carried out to study functional roles of Mg2+ binding to extracellular signal-regulated kinase 2 (ERK2). The results suggest that Mg2+ binding heavily decreases eigenvalue of the first principal component and totally inhibits motion strength of ERK2, which favors stabilization of ERK2 structure. Binding free energy predictions indicate that Mg2+ binding produces an important effect on binding ability of adenosine triphosphate (ATP) to ERK2 and strengthens the ATP binding. The calculations of residue-based free energy decomposition show that lack of Mg2+ weakens interactions between the hydrophobic rings of ATP and five residues I29, V37, A50, L105, and L154. Hydrogen bond analyses also prove that Mg2+ binding increases occupancies of hydrogen bonds formed between ATP and residues K52, Q103, D104, and M106. We expect that this study can provide a significant theoretical hint for designs of anticancer drugs targeting ERK2.