PMID- 21735122
OWN - NLM
STAT- MEDLINE
DCOM- 20120816
LR  - 20211020
IS  - 0948-5023 (Electronic)
IS  - 0948-5023 (Linking)
VI  - 18
IP  - 4
DP  - 2012 Apr
TI  - Evaluation of natural and nitramine binding energies to 3-D models of the S1S2 
      domains in the N-methyl-D-aspartate receptor.
PG  - 1273-84
LID - 10.1007/s00894-011-1152-y [doi]
AB  - 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 alpha-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.
FAU - Ford-Green, Jason
AU  - Ford-Green J
AD  - Interdisciplinary Center for Nanotoxicity, Jackson State University, Jackson, MS 
      39217, USA. jgreen@icnanotox.org
FAU - Isayev, Olexandr
AU  - Isayev O
FAU - Gorb, Leonid
AU  - Gorb L
FAU - Perkins, Edward J
AU  - Perkins EJ
FAU - Leszczynski, Jerzy
AU  - Leszczynski J
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20110707
PL  - Germany
TA  - J Mol Model
JT  - Journal of molecular modeling
JID - 9806569
RN  - 0 (Aniline Compounds)
RN  - 0 (Azocines)
RN  - 0 (NR1 NMDA receptor)
RN  - 0 (NR2A NMDA receptor)
RN  - 0 (Nitrobenzenes)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (Triazines)
RN  - GJ18911991 (nitramine)
RN  - LLW94W5BSJ (octogen)
RN  - W91SSV5831 (cyclonite)
SB  - IM
MH  - Amino Acid Sequence
MH  - Aniline Compounds/chemistry/*metabolism
MH  - Azocines/metabolism
MH  - Binding Sites
MH  - Humans
MH  - Models, Molecular
MH  - Molecular Dynamics Simulation
MH  - Molecular Sequence Data
MH  - Neurodegenerative Diseases/metabolism
MH  - Nitrobenzenes/chemistry/*metabolism
MH  - Protein Binding
MH  - Protein Conformation
MH  - Protein Structure, Tertiary
MH  - Receptors, N-Methyl-D-Aspartate/*chemistry/*metabolism
MH  - Sequence Alignment
MH  - Triazines/metabolism
EDAT- 2011/07/08 06:00
MHDA- 2012/08/17 06:00
CRDT- 2011/07/08 06:00
PHST- 2011/03/23 00:00 [received]
PHST- 2011/06/10 00:00 [accepted]
PHST- 2011/07/08 06:00 [entrez]
PHST- 2011/07/08 06:00 [pubmed]
PHST- 2012/08/17 06:00 [medline]
AID - 10.1007/s00894-011-1152-y [doi]
PST - ppublish
SO  - J Mol Model. 2012 Apr;18(4):1273-84. doi: 10.1007/s00894-011-1152-y. Epub 2011 
      Jul 7.