Molecular dynamic simulations of gabergic ciclic ketones: Interaction with membranes and their contrast with experimental results.

MIGUEL V; SANCHEZ BORZONE, M; GARCIA DA

Cordoba

Jornada; I Jornada Vincular para crecer. Camino hacia los 20 añosdel ICTA; 2015

ICTA. FCEFYN-Universidad Nacional de Córdoba.

The GABAA receptor (GABA-R) is the maininhibitory receptor of the Central Nervous System. It possesses binding sitesfor drugs other than the neurotransmitter GABA, including benzodiazepines,barbiturates, and the convulsing picrotoxine, which behave as allostericmodulators or channel blockers. The study of this last binding site isespecially relevant since it constitutes the target of widely used neurotoxicorganochlorine pesticides with agricultural importance. Our group has studiedsome highly lipophilic cyclic ketones demonstrating their ability to inhibitthe GABA-R activity. Many lipophilic compounds that regulate GABAA-R functionmay change the physical properties of the lipid bilayer. In the present work,we show Molecular Dynamics (MD) Simulation studies of the interaction of cyclicketones with gabaergic activity, using a model bilayer of1,2-dipalmitoyl-sn-glycero-3-phosphocholine (dpPC). Free diffusion MDsimulations of dpPC in presence of the different ketones were used to analyzetheir interaction with a bilayer. These studies revealed a looser packing inthe hydrocarbon chains of the dpPC in presence of these ketones. Additionally,we obtained spatially resolved free energy profiles of ketones partition intodpPC bilayers based on umbrella sampling. These profiles allowed us todetermine the most probable ketones-dpPC interaction site. MD simulationsresults were contrasted with experimental data and agreements were found.Fluorescence anisotropy studies with different probes (DPH and TMA-DPH)indicated that all compounds were able to increase the membrane fluidity in aconcentration dependent manner, and their effects were evidenced at differentdepth of the bilayer. Considering that the functions of proteins in themembrane might be altered as a result of the bilayer properties likeelasticity, fluidity, thinning, etc., it is expected that GABAA-R could be alsomodulated not only by the specific ligand recognition, but also by changes inthe physical state of the membrane