Effect of gabaergic phenols on the dynamic and structure of lipid bilayers: a molecular dynamic simulation approach

MIGUEL V; VILLARREAL MA; GARCÍA, DANIEL A.

San Luis

Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Biofísica; 2019

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the centralnervous system. GABAA receptors are activated by GABA and modulated by a widevariety of recognized drugs, including anesthetics and benzodiazepines. GABAergicphenols (GP) like propofol, thymol, chlorothymol, carvacrol and eugenol are positiveallosteric modulators of R-GABAA. These GP are lipophilic, therefore their anestheticactivity could be the combined result of their specific interaction with the receptor, aswell as nonspecific interactions with the receptor lipidic environment. We used moleculardynamic (MD) simulations to contribute to a description of the molecular events thatoccur at the membrane as part of the mechanism of general anesthesia. Previous MDsimulations indicated that GP interacts with the polar interface of phospholipid bilayer.The presence of GP in a DPPC bilayer has an ordering effect on lipid acyl chains forcarbons near the interface. We have now determined GP orientation in the bilayer bydefining a set of molecular axes. We have calculated the correlation of the experimentalmembrane partition coefficients obtained by the IAM?HPLC method (log kIAM?W), with ΔGof partition obtained in biased MD and obtained a value of 0.935. Potential of mean force(PMF) calculations using umbrella sampling were used to characterize the forces thatdrive propofol partition into the bilayer. This analysis showed that propofol partition ismainly enthalpic driven at the polar region and entropic driven at the hydrocarbonchains. We calculated the GP-water, GP-GP and GP-DPPC non-bonding interactions. Wefound attractive Lennard-Jones (LJ) interactions between phenol and DPPC, while GP-GPLJ forces were found to be nearly zero. Finally, we determined the first hydration shell forPRF. While in the aquose phase PRF has ~35 water molecules, at the lipid phase there isan average of ~5 water molecules, except at translocations, were water molecules dropto cero. These results confirm that all the GP studied interact with membranes, and exertsome alteration of the receptor lipid environment. Thus, it is possible that anestheticactivity of GPs could be the combined result of their interaction with specific receptorproteins (GABA-Rs) but also with the surrounding lipid molecules.