Localization, aggregation, and interaction of glycyrrhizic acid with the plasma membrane

Glycyrrhizic acid (GLA) is the most important bioactive constituent of licorize root and exhibits antiviral, antimicrobial, anti-oxidant, anti-inflammatory, anti-allergic, and antitumor activities. GLA has an amphiphilic nature consisting of two hydrophilic and one hydrophobic part, and its mechanism of action could be mediated by its incorporation into the membrane. Furthermore, GLA presents two different forms, protonated (GLA) and deprotonated (GLAD), and has been suggested that their location inside the membrane could be different. Since GLA could be a source against many types of diseases, we have localized the GLA molecule in the presence of a complex membrane and established the detailed interactions of GLA with lipids using all-atom molecular dynamics. Our outcomes sustain that GLA/GLAD tend to locate amid the CHOL oxygen atom and the phospholipid phosphates, preferably perpendicular to the membrane surface, increasing membrane fluidity. Interestingly, GLA and GLAD tend to be surrounded by specific phospholipids, different for each type of molecule. Outstandingly, both GLA and GLAD tend to spontaneously associate in solution forming aggregates, precluding them from inserting into the membrane and, therefore, interacting with it. Consequently, some of the biological properties of GLA/GLAD could be credited to the alteration of the membrane biophysical properties by interacting with specific lipids. However, the formation of an aggregate in solution could hinder its bioactive properties and should be considered a suited vehicle when prepared to be used in biological or clinical assays.