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

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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 γ2/α1 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.

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Acknowledgments

R.S.K.V thanks Council of Scientific and Industrial Research (CSIR), New Delhi for a Research Associateship. N.G. is thankful to CSIR Mission Mode Program (CMM-0017) for providing financial assistance. Software support granted by OpenEye is greatly acknowledged. We acknowledge Mr. Robert Schulz for providing scripts to generate Porcupine Plots.

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Authors and Affiliations

  1. Structural Biology and Bioinformatics Division, Indian Institute of Chemical Biology, (A unit of CSIR), 4 Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, India

    R. S. K. Vijayan & Nanda Ghoshal

  2. Biophysics Division, Saha Institute of Nuclear Physics, Sector-1, Block-AF, Bidhannagar, Kolkata, 700 064, India

    Dhananjay Bhattacharyya

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  1. R. S. K. Vijayan
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  2. Dhananjay Bhattacharyya
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  3. Nanda Ghoshal
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Correspondence to Nanda Ghoshal.

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Figure SI1

Plot of temperature, total energy and pressure as a function of time (DOC 110 kb)

Figure SI2

RMSF 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)

Figure SI3

Change in pore diameter plotted as a function of time for the vestibular region. (DOC 211 kb)

Figure SI4

Librational motion of the aromatic side chains of the BZ site during the MD simulation. (DOC 117 kb)

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Vijayan, R.S.K., Bhattacharyya, D. & Ghoshal, N. Deciphering the binding mode of Zolpidem to GABAA α1 receptor – insights from molecular dynamics simulation. J Mol Model 18, 1345–1354 (2012). https://doi.org/10.1007/s00894-011-1142-0

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  • DOI: https://doi.org/10.1007/s00894-011-1142-0

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