Clarifying binding difference of ATP and ADP to extracellular signal-regulated kinase 2 by using molecular dynamics simulations

Extracellular signal-regulated kinase 2 is a promising target for designs and development of anticancer drugs. Molecular dynamics simulations and molecular mechanics Poisson-Boltzmann method were applied to study binding difference of ADP and ATP to extracellular signal-regulated kinase 2. The results prove that the binding ability of ATP to extracellular signal-regulated kinase 2 is stronger than that of ADP. Principal component analysis performed by using molecular dynamics trajectories suggests that binding of ADP and ATP to extracellular signal-regulated kinase 2 change motion directions of two helices a1 and alpha 2. Residue-based free energy decomposition method was adopted to calculate contributions of separate residues to associations of ADP and ATP with extracellular signal-regulated kinase 2. The results show that ADP and ATP produce strong CH-pi interactions with five residues Ile29, Val37, Ala50, Leu105, and Leu154. In addition, five hydrogen bonding interactions of ADP and ATP with residues Lys52, Gln103, Asp104, and Met106 also stabilize bindings of ADP and ATP to extracellular signal-regulated kinase 2. Overall, the CH-pi interactions of ATP with five residues Ile29, Val37, Ala50, Leu105, and Leu154 are stronger than ADP. This study is expected to contribute a significant theoretical hint for designs of anticancer drugs targeting extracellular signal-regulated kinase 2.