How does a1Histidine102 affect the binding of modulators to a1b2c2 GABAA receptors? molecular insights from in silico experiments

Abstract

The activation of GABAAreceptors 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. GABAAreceptors are targets for numerous drugs, including benzodiazepines, which bind to α1β2γ2GABAAreceptors with high affinity to a site in the extracellular domain, between subunits α1and γ2. It has been established experimentally that the binding of these drugs depends on the presence of one particular amino acid in the α1subunit: histidine 102. However, the specific role it plays in the intermolecular interaction has not been elucidated. In this work, we appliedin silicomethods to understand whether certain protonation and rotamer states of α1His102 facilitate the binding of modulators. We analysed diazepam binding, a benzodiazepine, and the antagonist flumazenil to the GABAAreceptor 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 α1His102 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.