Journal of Molecular Modeling

, Volume 18, Issue 4, pp 1273–1284 | Cite as

Evaluation of natural and nitramine binding energies to 3-D models of the S1S2 domains in the N-methyl-D-aspartate receptor

  • Jason Ford-Green
  • Olexandr Isayev
  • Leonid Gorb
  • Edward J. Perkins
  • Jerzy Leszczynski
Original Paper


Overactivation of the N-methyl-D-aspartate receptor (NMDAR) in postsynaptic neurons leads to glutamate-related excitotoxicity in the central nervous system of mammals. We have built 3-D models of each domain for the universal screening of potential toxicants and their binding mechanisms. Our docking results show that the calculated pK i values of glycine and L-glutamate significantly increase (>1) when the NR1 and NR2A S1S2 domains are closing, respectively. Inversely, D-cycloserine (DCS) and 5,7-dichlorokynurenic acid (5,7-DCKA) do not show such a dependence on domain closure. Replica exchange molecular dynamics (REMD) confirmed 5 different conformational states of the S1S2 domain along the 308.2 K temperature trajectory. Analysis of residue fluctuations during this temperature trajectory showed that residues in loop 1, loop 2, the amino terminal domain (ATD), and the area linked to ion channel α-helices are involved in this movement. This further implicates the notion that efficacious ligands act through S1S2 lobe movement which can culminate in the opening or closing of the ion channel. We further tested this by docking hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocane (HMX) to the S1S2 domain. Our results predict that these nitramines are not efficacious and thus do not produce excitoxicity when they bind to the S1S2 domain of the NMDAR.


Homology modeling Molecular dynamics Molecular docking NMDAR RDX HMX 



The authors would like to thank Jacques Reifmann and the rest of his group at The Biotechnology High Performance Computing Software Application Institute (BHSAI) for their generous allotment of time, and the Army Research Laboratory (ARL) for the use of their computational resources. This work has been done under grant number W912HZ-09-C-0026. The use of trade, product, or firm names in this report is for descriptive purposes only and does not imply endorsement by the U.S. Government. Results in this study were funded and obtained from research conducted under the Environmental Quality Technology Program of the United States Army Corps of Engineers by the US Army ERDC. Permission was granted by the Chief of Engineers to publish this information. The findings of this report are not to be construed as an official Department of the Army position unless so designated by other authorized documents.

Supplementary material

894_2011_1152_MOESM1_ESM.doc (102 kb)
Fig. S1 a Ramachandran plot of the NR1 S1S2 3-D model before simulation. b Ramachandran plot of the NR2A S1S2 3-D model before simulation. c Ramachandran plot of the X-ray crystal structure 1pbq chain A [14]. (DOC 102 kb)
894_2011_1152_MOESM2_ESM.doc (76 kb)
Fig. S2 Root mean square deviation (RMSD in Å) versus time (ps) plots of a NR1 S1S2 3-D model over 4 ns and b NR2A S1S2 3-D model over 3 ns. Due to the increased flexibility observed for loops 1 and 2, the amino terminus (N), and the GT-linker regions of the NR1 S1S2 model we switched from a 2 fs time step to a 1 fs time step for the simulation of the NR2A S1S2 model. All simulations were done using the GB implicit solvent potential at 300K in the AMBER10 package. (DOC 76 kb)
894_2011_1152_MOESM3_ESM.doc (84 kb)
Fig. S3 Backbone alignment of the NR1 open structure from a classical MD simulation (blue) and the NR1 E conformer (tan) from the REMD simulation (5.20 Å RMSD) (DOC 84 kb)
894_2011_1152_MOESM4_ESM.doc (50 kb)
Table S1 Comparison of inhibition constants for the five different REMD conformations (DOC 49 kb)


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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Jason Ford-Green
    • 1
    • 2
  • Olexandr Isayev
    • 3
  • Leonid Gorb
    • 4
  • Edward J. Perkins
    • 2
  • Jerzy Leszczynski
    • 1
    • 2
  1. 1.Interdisciplinary Center for NanotoxicityJackson State UniversityJacksonUSA
  2. 2.Environmental Laboratory, US Army ERDCVicksburgUSA
  3. 3.Department of ChemistryCase Western Reserve UniversityClevelandUSA
  4. 4.Badger Technical ServicesSan AntonioUSA

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