IFISUR   23398
INSTITUTO DE FISICA DEL SUR
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
An in silico Approach towards a better understanding of GABAA receptors? structure/function relationship.
Autor/es:
JUAN FRANCISCO VISO; FERNANDO ZAMARREÑO; MARÍA J. AMUNDARAIN; MARCELO D. COSTABEL
Lugar:
San Miguel de Tucumán
Reunión:
Congreso; III Latin American Federation of Biophysical Societies; 2016
Institución organizadora:
Sociedad Argentina de Biofísica
Resumen:
The GABAARs, -Aminobutyric acid type A receptors, mediate fast inhibitorytransmission in the mammalian central nervous system. Theybelong to the pentameric ligand gated ion channels family along withserotonin type 3, nicotinic acetylcholine and glycine receptors. Theseanionic channels are pentameric ensembles of different subunits, andeach subtype has specific function and localization. They are the targetof many relevant compounds such as GABA, Benzodiazepines, Barbiturates,-carbolines and Neurosteroids(1). Due to their wide influencein neurological health it is essential to understand their structure andfunction thoroughly.We have previously developed a model of the beta2gamma2 subtype usinghomology modeling with the 3 homopentamer as a template (PDBID:4COF)(2). This structure is hypothesized to be in a closed desensitizedstate with high affinity for agonists. We evaluated the quality of themodel by doing molecular docking with a series of ligands from whichexperimental data is known about its binding mode. Molecular dynamicssimulations were performed with the aim of analyzing the stabilityof the receptor modeled and comparing its behavior with and withoutligands docked. In order to do so, we simulated the receptor alone, withone GABA molecule inserted in one of the orthosteric sites and withtwo molecules of GABA and Diazepam in their predicted binding sites.The structures remain stable along the 100 ns simulations, although minorstructural changes can be noticed. There are differences amongthe simulations with and without ligands, possibly related to conformationalchanges from the transition between the open/closed states. Inaddition, the behavior of the ligands is evaluated along the simulation,highlighting those interactions important for binding stability.We would like to thank CONICET and Universidad Nacional del Sur.