Molecular Dynamic Simulations of Gabaergic Ciclic Ketones: Interaction with membranes and their contrast with experimental results

MIGUEL V; SANCHEZ-BORZONE M; GARCÍA DA

Congreso; XLIV Reunion Anual de la Sociedad Argentina de Biofisica; 2015

TheGABAA receptor (GABA-R) is the main inhibitory receptor of the Central NervousSystem. It possesses binding sites for drugs other than the neurotransmitterGABA, including benzodiazepines, barbiturates, and the convulsing picrotoxine,which behave as allosteric modulators or channel blockers. The study of thislast binding site is especially relevant since it constitutes the target ofwidely used neurotoxic organochlorine pesticides with agricultural importance. Ourgroup has studied some highly lipophilic cyclic ketones demonstrating theirability to inhibit the GABA-R activity. Many lipophilic compounds that regulateGABAA-R function may change the physical properties of the lipid bilayer. Inthe present work, we show Molecular Dynamics (MD) Simulation studies of theinteraction of cyclic ketones 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 analyze theirinteraction with a bilayer. These studies revealed a looser packing in thehydrocarbon chains of the dpPC in presence of these ketones. Additionally, weobtained 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 agreements werefound. Fluorescence anisotropy studies with different probes (DPH and TMA-DPH) indicatedthat 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.