Insights into the Relationships Between Herbicide Activities, Molecular Structure and Membrane Interaction of Cinnamon and Citronella Essential Oils Components.

Since the 50's, the massive and "environmental naïve" use of synthetic chemistry has revolutionized the farming community facing the dramatic growth of demography. However, nowadays, the controversy grows regarding the long-term harmful effects of these products on human health and the environment. In this context, the use of essential oils (EOs) could be an alternative to chemical products and a better understanding of their mode of biological action for new and optimal applications is of importance. Indeed, if the biocidal effects of some EOs or their components have been at least partly elucidated at the molecular level, very little is currently known regarding their mechanism of action as herbicides at the molecular level. Here, we showed that cinnamon and Java citronella essential oils and some of their main components, i.e.,, cinnamaldehyde (CIN), citronellal (CitA), and citronellol (CitO) could act as efficient herbicides when spread on A. thaliana leaves. The individual EO molecules are small amphiphiles, allowing for them to cross the mesh of cell wall and directly interact with the plant plasma membrane (PPM), which is one of the potential cellular targets of EOs. Hence, we investigated and characterized their interaction with biomimetic PPM while using an integrative biophysical approach. If CitO and CitA, maintaining a similar chemical structure, are able to interact with the model membranes without permeabilizing effect, CIN belonging to the phenylpropanoid family, is not. We suggested that different mechanisms of action for the two types of molecules can occur: while the monoterpenes could disturb the lipid organization and/or domain formation, the phenylpropanoid CIN could interact with membrane receptors.

Mobility and Core-Protein Binding Patterns of Disordered C-Terminal Tails in ß-Tubulin Isotypes.

Although they play a significant part in the regulation of microtubule structure, dynamics, and function, the disordered C-terminal tails of tubulin remain invisible to experimental structural methods and do not appear in the crystallographic structures that are currently available in the Protein Data Bank. Interestingly, these tails concentrate most of the sequence variability between tubulin isotypes and are the sites of the principal post-translational modifications undergone by this protein. Using homology modeling, we developed two complete models for the human αI/ßI- and αI/ßIII-tubulin isotypes that include their C-terminal tails. We then investigated the conformational variability of the two ß-tails using long time-scale classical molecular dynamics simulations that revealed similar features, notably the unexpected presence of common anchoring regions on the surface of the tuulin dimer, but also distinctive mobility or interaction patterns, some of which could be related to the tail lengths and charge distributions. We also observed in our simulations that the C-terminal tail from the ßI isotype, but not the ßIII isotype, formed contacts in the putative binding site of a recently discovered peptide that disrupts microtubule formation in glioma cells. Hindering the binding site in the ßI isotype would be consistent with this peptide's preferential disruption of microtubule formation in glioma, whose cells overexpress ßIII, compared to normal glial cells. While these observations need to be confirmed with more intensive sampling, our study opens new perspectives for the development of isotype-specific chemotherapy drugs.

Investigating the Structural Variability and Binding Modes of the Glioma Targeting NFL-TBS.40-63 Peptide on Tubulin.

NFL-TBS.40-63 is a 24 amino acid peptide corresponding to the tubulin-binding site located on the light neurofilament subunit, which selectively enters glioblastoma cells, where it disrupts their microtubule network and inhibits their proliferation. We investigated its structural variability and binding modes on a tubulin heterodimer using a combination of NMR experiments, docking, and molecular dynamics (MD) simulations. Our results show that, while lacking a stable structure, the peptide preferentially binds on a specific single site located near the ß-tubulin C-terminal end, thus giving us precious hints regarding the mechanism of action of the NFL-TBS.40-63 peptide's antimitotic activity at the molecular level.