An In Silico approach towards a better understanding of GABAA receptors' structure/function relationship.

JUAN FRANCISCO VISO; FERNANDO ZAMARREÑO; MARÍA JULIA AMUNDARAIN; MARCELO DANIEL COSTABEL

San Miguel de Tucumán

Congreso; III Latin American Federation of Biophysical Societies (LAFeBS) ? IX IberoAmerican Congress of Biophysics ? XLV Reunión Anual SAB 2016; 2016

Universidad Nacional del Tucumán - Sociedad Argentina de Biofísica

The GABAARs, gamma-Aminobutyric acid type A receptors, mediate fast inhibitory transmission in the mammalian central nervous system. They belong to the pentameric ligand gated ion channels family along with serotonin type 3, nicotinic acetylcholine and glycine receptors. These anionic channels are pentameric ensembles of different subunits, and each subtype has specific function and localization. They are the target of many relevant compounds such as GABA, Benzodiazepines, Barbiturates, β-carbolines and Neurosteroids.1 Due to their wide influence in neurological health it is essential to understand their structure and function thoroughly.We have previously developed a model of the alpha1beta2gamma2 subtype using homology modeling with the β3 homopentamer as a template (PDBID: 4COF)2. This structure is hypothesized to be in a closed desensitized state with high affinity for agonists. We evaluated the quality of the model by doing molecular docking with a series of ligands from which experimental data is known about its binding mode. Molecular dynamics simulations were performed with the aim of analyzing the stability of the receptor modeled and comparing its behavior with and without ligands docked. In order to do so, we simulated the receptor alone, with one GABA molecule inserted in one of the orthosteric sites and with two molecules of GABA and Diazepam in their predicted binding sites. The structures remain stable along the 100 ns simulations, although minor structural changes can be noticed. There are differences among the simulations with and without ligands, possibly related to conformational changes from the transition between the open/closed states. In addition, the behavior of the ligands is evaluated along the simulation, highlighting those interactions important for binding stability.Referencias1. Sieghart W. Pharmacol. Rev. 47,181?234, 1995.2. Miller P.S., et al. Nature 512, 270?275, 2014.