How does α1Histidine102 affect the binding of modulators to α1β2γ2 GABAA receptors? molecular insights from in silico experiments

The activation of GABA(A) receptors by the neurotransmitter gamma-aminobutyric acid mediates the rapid inhibition response in the central nervous system of mammals. Many neurological and mental health disorders arise from alterations in the structure or function of these pentameric ion channels. GABA(A) receptors are targets for numerous drugs, including benzodiazepines, which bind to alpha(1)beta(2)gamma(2) GABA(A) receptors with high affinity to a site in the extracellular domain, between subunits alpha(1) and gamma(2). It has been established experimentally that the binding of these drugs depends on the presence of one particular amino acid in the alpha(1) subunit: histidine 102. However, the specific role it plays in the intermolecular interaction has not been elucidated. In this work, we applied in silico methods to understand whether certain protonation and rotamer states of alpha(1)His102 facilitate the binding of modulators. We analysed diazepam binding, a benzodiazepine, and the antagonist flumazenil to the GABA(A) receptor using molecular dynamics simulations and adaptive biasing force simulations. The binding free energy follows changes in the protonation state for both ligands, and rotameric states of alpha(1)His102 were specific for the different compounds, suggesting distinct preferences for positive allosteric modulators and antagonists. Moreover, in the presence of diazepam and favoured by a neutral tautomer, we identified a water molecule that links loops A, B, and C and may be relevant to the modulation mechanism.

Automated summary

The activation of GABA(A) receptors by the neurotransmitter gamma-aminobutyric acid mediates rapid inhibition response in the mammalian central nervous system. Alterations in these receptors can lead to various neurological and mental health disorders, with drugs like benzodiazepines targeting these receptors. It has been found that a specific amino acid in the alpha(1) subunit plays a role in drug binding, impacting the binding free energy and preferences for different ligands. Additionally, molecular dynamics simulations revealed water molecules that may play a role in the modulation mechanism of these receptors.