Cross-talk between allosteric and orthosteric binding sites of γ-amino butyric acid type A receptors (GABA_A-Rs): A computational study revealing the structural basis of selectivity

Abstract

The γ-amino butyric acid type A receptors (GABA_A-Rs) are GABA-gated chloride ion channels that mediate fast inhibitory neurotransmissions. Due to their essential role in normal brain function, neuromodulatory therapies are targeted at them for restoring GABA-mediated inhibition. The receptor modulation by benzodiazepine (BZD) shows therapeutically useful actions. The mechanisms, by which BZD-site performs selective transduction while modulating GABA_A-Rs, and its correlation with the occurrence of sedation is not fully known. In pursuance, we performed a computational study starting from modeling of α₂-subtype GABA_A-R, docking of α_1/2-selective ligands followed by molecular dynamics simulations of the obtained complexes. The results show that during early stages of activation, a) allosteric binding initiate structural changes through BZD-site for GABA-elicited activation; b) selective BZD-binders positively modulate orthosteric GABA-bound site with fin-like C- and F-loop movements, which supports twisting of inner and outer β-barrel; c) modulation by α_1/2-selective ligands was only evident at site 1, mimicking mandatory doubly bound state; d) strength of allosteric communication was prominent for α₂-modulators, however, the basic nature of allosteric-orthosteric site cross-talk remains same for both α_1/2-modulators; and e) ratio of hydrophobic:hydrophilic ligand contact surface decides α₂-selectivity, less value of ratio favors it. These insights would enable us to design better α₂-selective modulator/s. Altogether our computational study reveals early stages of allosteric modulation, highlighting subtype selective activation and pathways recommending GABA binding sites during selective modulation.

Communicated by Ramaswamy H. Sarma

Keywords:

• GABAA-Rs
• benzodiazepine site
• selective allosteric modulation
• molecular dynamics simulations
• anxioselective drugs

Acknowledgements

Authors thank CSIR Centre for Mathematical Modelling and Computer Simulation (C-MMACS), Bangalore, for providing computational facility to perform most of our MD simulations. Authors thank Mrs. Puja Berad Payghan for her help in reference formatting.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Council of Scientific and Industrial Research (CSIR), New Delhi under E.S. grant [sanction letter no. 21(0918)/12/EMR-II]. P.V.P thanks CSIR for providing Senior Research Fellowship under E.S. scheme of Dr. Nanda Ghoshal.