Research Article: Effects of gabergic phenols on the dynamic and structure of lipid bilayers: A molecular dynamic simulation approach

Date Published: June 25, 2019

Publisher: Public Library of Science

Author(s): Virginia Miguel, Marcos A. Villarreal, Daniel A. García, Claudio M. Soares.

http://doi.org/10.1371/journal.pone.0218042

Abstract

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the vertebrate and invertebrate nervous system. GABAA receptors are activated by GABA and their agonists, and modulated 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. These GABAergic phenols interact with the lipid membrane, therefore, their anesthetic activity could be the combined result of their specific activity (with receptor proteins) as well as nonspecific interactions (with surrounding lipid molecules) modulating the supramolecular organization of the receptor environment. Therefore, we aimed to contribute to a description of the molecular events that occur at the membrane level as part of the mechanism of general anesthesia, using a molecular dynamic simulation approach. Equilibrium molecular dynamics simulations indicate that the presence of GABAergic phenols in a DPPC bilayer orders lipid acyl chains for carbons near the interface and their effect is not significant at the bilayer center. Phenols interacts with the polar interface of phospholipid bilayer, particularly forming hydrogen bonds with the glycerol and phosphate group. Also, potential of mean force calculations using umbrella sampling show that propofol partition is mainly enthalpic driven at the polar region and entropic driven at the hydrocarbon chains. Finally, potential of mean force indicates that propofol partition into a gel DPPC phase is not favorable. Our in silico results were positively contrasted with previous experimental data.

Partial Text

GABAA receptors (GABA-Rs) are ligand-gated ion channels that mediate rapid synaptic inhibition and they constitute the main inhibitory receptors of the Central Nervous System. GABA-Rs are membrane intrinsic proteins with specific binding sites for drugs other than the neurotransmitter GABA, that includes benzodiazepines, barbiturates, and the convulsant picrotoxinin, which behave as allosteric modulators or channel blockers [1]. Propofol (PRF) is a phenol widely used as intravenous general anesthetic [2]. PRF and the related phenol thymol have been shown to act on R-GABA as allosteric modulators at low concentrations or to have a direct effect on the channel opening at high concentrations. These activities are mediated by their interaction with a specific site in the GABA-R [3, 4]. However, a non-specific effect on the receptor modulation cannot be discarded taking into account the lipophilicity of these compounds and their interaction with the membrane surrounding the receptor [5, 6]. In fact, it is known that the activity of this receptor may be affected by surface-active compounds and by physical changes in the membrane [7–9].

Equilibrium MD and PMF simulations indicate that GP interact with the polar interface of phospholipid bilayer, particularly forming hydrogen bonds with the glycerol and phosphate group. Previously, we have investigated the effects of the insertion and the possible preferential location of the five phenol derivatives with GABAergic activity on membranes, using Langmuir monolayers and 1H-NMR spectroscopy [8, 22]. We determined that all compounds locate in the region between the polar group (choline molecule), the glycerol and the first atoms of the acyl chains, with the more lipophilic compounds (PRF and chlorothymol) preferring a deeper bilayer insertion [8, 22]. Our MD results, in agreement with previous experimental data, indicate that the location of the phenol molecules would allow a closer molecular packing diminishing the mobility of the hydrocarbon chains. Experimental assays using Langmuir films in the presence of each GP indicate a combined effect of GPs condensing the LE phase, and expanding the LC phase [8]. This effect results in a broadening of the phase transition in the Langmuir isotherm [8].

 

Source:

http://doi.org/10.1371/journal.pone.0218042

 

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