Prediction of GluN2B-CT 1290-1310/DAPK1 Interaction by Protein⁻Peptide Docking and Molecular Dynamics Simulation

Molecules. 2018 Nov 19;23(11):3018. doi: 10.3390/molecules23113018.


The interaction of death-associated protein kinase 1 (DAPK1) with the 2B subunit (GluN2B) C-terminus of N-methyl-D-aspartate receptor (NMDAR) plays a critical role in the pathophysiology of depression and is considered a potential target for the structure-based discovery of new antidepressants. However, the 3D structures of C-terminus residues 1290⁻1310 of GluN2B (GluN2B-CT1290-1310) remain elusive and the interaction between GluN2B-CT1290-1310 and DAPK1 is unknown. In this study, the mechanism of interaction between DAPK1 and GluN2B-CT1290-1310 was predicted by computational simulation methods including protein⁻peptide docking and molecular dynamics (MD) simulation. Based on the equilibrated MD trajectory, the total binding free energy between GluN2B-CT1290-1310 and DAPK1 was computed by the mechanics generalized born surface area (MM/GBSA) approach. The simulation results showed that hydrophobic, van der Waals, and electrostatic interactions are responsible for the binding of GluN2B-CT1290⁻1310/DAPK1. Moreover, through per-residue free energy decomposition and in silico alanine scanning analysis, hotspot residues between GluN2B-CT1290-1310 and DAPK1 interface were identified. In conclusion, this work predicted the binding mode and quantitatively characterized the protein⁻peptide interface, which will aid in the discovery of novel drugs targeting the GluN2B-CT1290-1310 and DAPK1 interface.

Keywords: DAPK1-GluN2B peptide; MD simulation; binding free energy; hotspot; protein–peptide docking.

MeSH terms

  • Death-Associated Protein Kinases*
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation*
  • Protein Binding
  • Receptors, N-Methyl-D-Aspartate*
  • Thermodynamics


  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Death-Associated Protein Kinases