Journal of Molecular Modeling

, Volume 18, Issue 4, pp 1345–1354

Deciphering the binding mode of Zolpidem to GABAA α1 receptor – insights from molecular dynamics simulation

  • R. S. K. Vijayan
  • Dhananjay Bhattacharyya
  • Nanda Ghoshal
Original Paper

Abstract

To investigate the binding mode of Zolpidem to GABAA and to delineate the conformational changes induced upon agonist binding, we carried out atomistic molecular dynamics simulation using the ligand binding domain of GABAA α1 receptor. Comparative molecular dynamics simulation of the apo and the holo form of GABAA receptor revealed that γ21 interface housing the benzodiazepine binding site undergoes distinct conformational changes upon Zolpidem binding. We notice that C loop of the α1 subunit experiences an inward motion toward the vestibule and the F loop of γ2 sways away from the vestibule, an observation that rationalizes Zolpidem as an alpha1 selective agonist. Energy decomposition analysis carried out was able to highlight the important residues implicated in Zolpidem binding, which were largely in congruence with the experimental data. The simulation study disclosed herein provides a meaningful insight into Zolpidem-GABAAR interactions and helps to arrive at a binding mode hypothesis with implications for drug design.

Keywords

Molecular dynamics GABAA α1 receptor Docking 

Supplementary material

894_2011_1142_MOESM1_ESM.doc (110 kb)
Figure SI1Plot of temperature, total energy and pressure as a function of time (DOC 110 kb)
894_2011_1142_MOESM2_ESM.doc (102 kb)
Figure SI2RMSF values of the Cα atoms for the chain B (β2), chain C (α1) and D (β2) of the apo form (red) and holo form (green) (DOC 102 kb)
894_2011_1142_MOESM3_ESM.doc (211 kb)
Figure SI3Change in pore diameter plotted as a function of time for the vestibular region. (DOC 211 kb)
894_2011_1142_MOESM4_ESM.doc (117 kb)
Figure SI4Librational motion of the aromatic side chains of the BZ site during the MD simulation. (DOC 117 kb)

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • R. S. K. Vijayan
    • 1
  • Dhananjay Bhattacharyya
    • 2
  • Nanda Ghoshal
    • 1
  1. 1.Structural Biology and Bioinformatics DivisionIndian Institute of Chemical Biology, (A unit of CSIR)KolkataIndia
  2. 2.Biophysics DivisionSaha Institute of Nuclear PhysicsKolkataIndia

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