MOLECULAR DYNAMIC SIMULATIONS OF GABERGIC CICLIC KETONES

MIGUEL, V; SANCHEZ BORZONE, M; GARCIA, DA

Santiago del Estero

Congreso; XLIV Reunión Anual Sociedad Argentina de Biofísica; 2015

Sociedad Argentina de Biofísica

MOLECULARDYNAMIC SIMULATIONS OF GABERGIC CICLIC KETONES: Interaction with membranes andtheir contrast with experimental results.GABAA receptors (GABAA-R) are ligand-gated ion channels with binding sites for drugs other than the neurotransmitter GABA, including benzodiazepines, barbiturates, and the anticonvulsantpicrotoxinin. These molecules behave as allosteric modulators or channel blockers. The study of picrotoxinin site is especially relevant since it constitutes the action site of widely used neurotoxic organichlorine pesticides.  Our group has studied some highly lipophilic cyclic ketones demonstrating their ability to inhibit the GABA-R activity. Many lipophilic compounds that regulate GABA-R function may change the physical properties of the lipid bilayer. In the present work, we show Molecular Dynamics (MD) Simulationstudies of the interaction of cyclic ketones, with gabaergic activity, using amodel bilayer of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (dpPC). Freediffusion MD simulations of dpPC in presence of the different ketones were usedto analyze their interaction with a bilayer. These studies revealed a looserpacking in the hydrocarbon chains of the dpPC in presence of these ketones. Additionally,we obtained spatially resolved free energy profiles of ketones partition into dpPCbilayers based on umbrella sampling. These profiles allowed us to determine themost probable Ketones-dpPC interaction site. MDsimulations results were contrasted with experimental data and the agreementswere found. Fluorescence anisotropy studies with different probes (DPH andTMA-DPH) indicated that all compounds were able to increase the membranefluidity in a concentration dependent manner, and their effects were evidencedat different depth of the bilayer. Considering that the functions of proteinsin 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. Acknowledgements: This work wassupported by grants from SECyT-UNC, FONCYT-MinCyT and CONICET.