Abstract
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.
Highlights
It has been estimated that depression will be the second largest global health burden among all disorders by 2030 [1,2,3]
In the medial prefrontal cortex was recently found to contribute to the development of depressive-like behavior [16,17], and several studies have confirmed that death-associated protein kinase 1 (DAPK1) is a promising target for the treatment of strokes, especially to prevent neuronal apoptosis in neuronal cell death [18,19,20]
The representative structure was generated by of 100 snapshots taken from the period of 40–50 ns of the trajectory A molecular dynamics (MD) simulation
Summary
It has been estimated that depression will be the second largest global health burden among all disorders by 2030 [1,2,3]. The interaction between death-associated protein kinase 1 (DAPK1) and the C-terminus of the 2B subunit (GluN2B) of the N-methyl-D-aspartate receptor (NMDAR) is reported to potentiate the activity of NR2B-containing NMDAR (NR2BR) [13,14,15]. Molecules 2018, 23, 3018 phosphorylation of NR2B subunit at Ser-1303, it induces injurious Ca2+ influx through NMDA receptor channels and leads to irreversible neuronal death [13,14,15]. The interaction between DAPK1 and GluN2B in the medial prefrontal cortex was recently found to contribute to the development of depressive-like behavior [16,17], and several studies have confirmed that DAPK1 is a promising target for the treatment of strokes, especially to prevent neuronal apoptosis in neuronal cell death [18,19,20]
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