Interaction of Thymol with Cell Membranes Models Studied with Tensiometry, Vibrational Spectroscopy and Molecular Simulation

Abstract

Thymol (2-isopropyl-5-methylphenol) is a natural compound that acts as a microbicide, with a probable effect on cell membrane surfaces. However, the mechanism of action when it interacts with lipid surfaces is not sufficiently known. For this reason, it is important to understand at the molecular level interactions between the drug and biointerfaces, and using models for cell membranes can be an appropriate strategy for this purpose. In this study, we employed Langmuir monolayers of lipids as cell membrane models, with the drug incorporated in monolayers of zwitterionic lipids, namely DPPC (dipalmitoyl phosphatidyl choline), and negative lipids, namely DPPS (dipalmitoyl phosphatidyl serine), and compared to data obtained with Molecular Simulation. Combining data on Surface Pressure-Area Isotherms with Polarization Modulation Infrared Reflection-Absorption Spectroscopy (PM-IRRAS), the effect of the thymol on lipid monolayers was compared by in view of the chemical and molecular structure of the lipids and the drug. The adsorption of the drug at the monolayers decreases the order of the lipid film, in a molecular mechanism that involves both polar head groups and alkyl tails from the lipids. Also the adsorption of thymol is modulated by the lipid monolayer composition since it adsorbed in a higher extend in negative charged lipid monolayers. Data obtained from Molecular Simulation corroborate with Langmuir monolayer experiments suggesting specific sites of interaction between lipid and drug. A model is then proposed in which thymol interacts with lipids at the air-water in such a way that the interactions are maximized owing to geometrical adaptations on behalf of the contact between specific groups between the lipid and the drug.