CONICET | Buscador de Institutos y Recursos Humanos

GABAA receptors (GABAA-R) are ligand-gated ion channels with binding sites for drugs other than the neurotransmitter GABA, including benzodiazepines, barbiturates, and alcohols. These molecules behave as allosteric modulators or channel blockers. There is still considerable debate about the molecular mechanism by which anesthetics induce sedation. Many lipophilic compounds that regulate GABA-R function can change the physical properties of the lipid bilayer. Considering that the functions of proteins in the membrane might be altered as a result of the bilayer properties like elasticity, fluidity, thinning, etc., it is expected that GABAA-R could be also modulated not only by the specific ligand recognition, but also by changes in the physical state of the membrane. The intravenous anesthetic Propofol modulates the lipid phase transition with an effect analogous to that of cholesterol. In the present work, we obtained spatially resolved free energy profiles of partition into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayers of Propofol and phenols with GABAergic activity, based on umbrella sampling. These profiles allowed us to determine the most probable phenols-DPPC interaction site. Also, we show Molecular Dynamics (MD) simulation studies of the interaction of phenols, using a model bilayer of DPPC. Free diffusion MD simulations of DPPC in presence of the different phenols were used to analyze their interaction with a bilayer. These studies revealed a tighter packing in the hydrocarbon chains of the DPPC in presence of these compounds. The simulations reveal that GABAergic phenols have a cholesterol-like ordering effect on DPPC in the fluid phase, as proved before for Propofol.