Journal of Molecular Modeling

, Volume 10, Issue 5, pp 305–316

Evolutionary trace analysis of ionotropic glutamate receptor sequences and modeling the interactions of agonists with different NMDA receptor subunits


  • Mathias-Costa Blaise
    • Department of PsychopharmacologyNational Institute of Mental Health and Neuro Sciences (NIMHANS)
  • Ramanathan Sowdhamini
    • National Centre for Biological Sciences (NCBS)TIFR
  • Metpally Raghu Prasad Rao
    • National Centre for Biological Sciences (NCBS)TIFR
    • Department of PsychopharmacologyNational Institute of Mental Health and Neuro Sciences (NIMHANS)
Original Paper

DOI: 10.1007/s00894-004-0196-7

Cite this article as:
Blaise, M., Sowdhamini, R., Rao, M.R.P. et al. J Mol Model (2004) 10: 305. doi:10.1007/s00894-004-0196-7


The ionotropic N-methyl-d-aspartate (NMDA) receptor is of importance in neuronal development, functioning, and degeneration in the mammalian central nervous system. The functional NMDA receptor is a heterotetramer comprising two NR1 and two NR2 or NR3 subunits. We have carried out evolutionary trace (ET) analysis of forty ionotropic glutamate receptor (IGRs) sequences to identify and characterize the residues forming the binding socket. We have also modeled the ligand binding core (S1S2) of NMDA receptor subunits using the recently available crystal structure of NR1 subunit ligand binding core which shares ~40% homology with other NMDA receptor subunits. A short molecular dynamics simulation of the glycine-bound form of wild-type and double-mutated (D481N; K483Q) NR1 subunit structure shows considerable RMSD at the hinge region of S1S2 segment, where pore forming transmembrane helices are located in the native receptor. It is suggested that the disruption of domain closure could affect ion-channel activation and thereby lead to perturbations in normal animal behavior. In conclusion, we identified the amino acids that form the ligand-binding pocket in many ionotropic glutamate receptors and studied their hydrogen bonded and nonbonded interaction patterns. Finally, the disruption in the S1S2 domain conformation (of NR1 subunit- crystal structure) has been studied with a short molecular dynamics simulation and correlated with some experimental observations.

Figure The figure shows the binding mechanism of glutamate with NR2B subunit of the NMDA receptor. Glutamate is shown in cpk, hydrogen bonds in dotted lines and amino acids in blue. The amino acids shown here are within a 4-Å radius of the ligand (glutamate)


NMDALigand binding coreS1S2 segmentET analysisHomology modelingHydrogen bonding

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© Springer-Verlag 2004