title: Functional roles of magnesium binding to extracellular signal-regulated kinase 2 explored by molecular dynamics simulations and principal component analysis.
abstract: 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.
authors.affiliation: a School of Science, Shandong Jiaotong University , Jinan 250357 , China.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Chen
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry*; D001665:Binding Sites; D006801:Humans; D006860:Hydrogen Bonding / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions / Q000187:drug effects; D008274:Magnesium / Q000737:chemistry*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy; D025341:Principal Component Analysis; D011485:Protein Binding
chemical_list: D000255:Adenosine Triphosphate; D019950:Mitogen-Activated Protein Kinase 1; D008274:Magnesium
keywords: Mg2+ binding; binding free energy; extracellular signal-regulated kinase 2; molecular dynamics simulation; principal component analysis