Effects of gabergic phenols on the dynamic and structure of lipid bilayers. A molecular dynamic simulation approach

MIGUEL V; VILLARREAL MA; GARCÍA, DANIEL A.

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2019

1932-6203

γ-Aminobutyricacid (GABA) is the major inhibitory neurotransmitter in the vertebrate and invertebrate nervous system. GABAA receptors  are activated by GABA and their agonists, andmodulated by a wide variety of recognized drugs, including barbiturates,anesthetics, and benzodiazepines. The phenols propofol, thymol, chlorothymol,carvacrol and eugenol act as positive allosteric modulators on GABAA-R receptor. TheseGABAergic phenols interact with the lipid membrane, therefore, their anestheticactivity could be the combined result of their specific activity (with receptorproteins) as well as nonspecific interactions (with surrounding lipidmolecules) modulating the supramolecular organization of the receptorenvironment. Therefore, we aimed to contribute to a description of themolecular events that occur at the membrane level as part of the mechanism ofgeneral anesthesia, using a molecular dynamic simulation approach.  Equilibrium molecular dynamics simulationsindicate that the presence of GABAergic phenols in a DPPC bilayer orders lipidacyl chains for carbons near the interface and their effect is not significantat the bilayer center. Phenols interacts with the polar interface ofphospholipid bilayer, particularly forming hydrogen bonds with the glycerol andphosphate group. Also, potential of mean force calculations using umbrellasampling show that propofol partition is mainly enthalpic driven at the polarregion and entropic driven at the hydrocarbon chains. Finally, potential ofmean force indicates that propofol partition into a gel DPPC phase is notfavorable. Our in silico results werepositively contrasted with previous experimental data.