Interaction of gabaergic ketones with model membranes: A molecular dynamics and experimental approach.

Autor: Miguel V; Universidad Nacional de Córdoba, Facultad de Ciencias Exactas, Físicas y Naturales, Departamento de Química, Cátedra de Química Biológica, Córdoba, Argentina; Instituto de Investigaciones Biológicas y Tecnológicas (IIBYT), CONICET-Universidad Nacional de Córdoba, Córdoba, Argentina., Sánchez-Borzone ME; Universidad Nacional de Córdoba, Facultad de Ciencias Exactas, Físicas y Naturales, Departamento de Química, Cátedra de Química Biológica, Córdoba, Argentina; Instituto de Investigaciones Biológicas y Tecnológicas (IIBYT), CONICET-Universidad Nacional de Córdoba, Córdoba, Argentina., García DA; Universidad Nacional de Córdoba, Facultad de Ciencias Exactas, Físicas y Naturales, Departamento de Química, Cátedra de Química Biológica, Córdoba, Argentina; Instituto de Investigaciones Biológicas y Tecnológicas (IIBYT), CONICET-Universidad Nacional de Córdoba, Córdoba, Argentina. Electronic address: dagarcia@unc.edu.ar.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Biomembranes [Biochim Biophys Acta Biomembr] 2018 Aug; Vol. 1860 (8), pp. 1563-1570. Date of Electronic Publication: 2018 May 25.
DOI: 10.1016/j.bbamem.2018.05.012
Abstrakt: γ-Aminobutyric-acid receptor (GABA A -R), a membrane intrinsic protein, is activated by GABA and modulated by a wide variety of recognized drugs. GABA A -R is also target for several insecticides which act by recognition of a non-competitive blocking site. Mentha oil is rich in several ketones with established activity against various insects/pests. Considering that mint ketones are highly lipophilic, their action mechanism could involve, at least in part, a non-specific receptor modulation by interacting with the surrounding lipids. In the present work, we studied in detail the effect on membranes of five cyclic ketones present in mint plants, with demonstrated insecticide and gabaergic activity. Particularly, we have explored their effect on the organization and dynamics of the membrane, by using Molecular Dynamics (MD) Simulation studies in a bilayer model of DPPC. We performed free diffusion MD and obtained spatially resolved free energy profiles of ketones partition into bilayers based on umbrella sampling. The most favored location of ketones in the membrane corresponded to the lower region of the carbonyl groups. Both hydrocarbon chains were slightly affected by the presence of ketones, presenting an ordering effect for the methylene groups closer to the carbonyl. MD simulations results were also contrasted with experimental data from fluorescence anisotropy studies which evaluate changes in membrane fluidity. In agreement, these assays indicated that the presence of ketones between lipid molecules induced an enhancement of the intermolecular interaction, increasing the molecular order throughout the bilayer thickness.
(Copyright © 2018 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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