Format

Send to

Choose Destination
Molecules. 2018 Nov 19;23(11). pii: E3018. doi: 10.3390/molecules23113018.

Prediction of GluN2B-CT1290-1310/DAPK1 Interaction by Protein⁻Peptide Docking and Molecular Dynamics Simulation.

Tu G1,2, Fu T3,4, Yang F5,6, Yao L7, Xue W8, Zhu F9,10.

Author information

1
Innovative Drug Research and Bioinformatics Group, School of Pharmaceutical Sciences and Collaborative Innovation Center for Brain Science, Chongqing University, Chongqing 401331, China. tugao@cqu.edu.cn.
2
Innovative Drug Research and Bioinformatics Group, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. tugao@cqu.edu.cn.
3
Innovative Drug Research and Bioinformatics Group, School of Pharmaceutical Sciences and Collaborative Innovation Center for Brain Science, Chongqing University, Chongqing 401331, China. 20162902031@cqu.edu.cn.
4
Innovative Drug Research and Bioinformatics Group, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. 20162902031@cqu.edu.cn.
5
Innovative Drug Research and Bioinformatics Group, School of Pharmaceutical Sciences and Collaborative Innovation Center for Brain Science, Chongqing University, Chongqing 401331, China. kristen@cqu.edu.cn.
6
Innovative Drug Research and Bioinformatics Group, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. kristen@cqu.edu.cn.
7
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA. ballad2006@163.com.
8
Innovative Drug Research and Bioinformatics Group, School of Pharmaceutical Sciences and Collaborative Innovation Center for Brain Science, Chongqing University, Chongqing 401331, China. xueww@cqu.edu.cn.
9
Innovative Drug Research and Bioinformatics Group, School of Pharmaceutical Sciences and Collaborative Innovation Center for Brain Science, Chongqing University, Chongqing 401331, China. zhufeng@cqu.edu.cn.
10
Innovative Drug Research and Bioinformatics Group, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. zhufeng@cqu.edu.cn.

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.

KEYWORDS:

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

PMID:
30463177
PMCID:
PMC6278559
DOI:
10.3390/molecules23113018
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Multidisciplinary Digital Publishing Institute (MDPI) Icon for PubMed Central
Loading ...
Support Center