Gabaergic insecticides exploration: interaction with biological membranes. An experimental and in silico approach.

GASTALDI MS; SANCHEZ-BORZONE M; GARCÍA DA; MIGUEL V

Congreso; XLIX Reunión Anual Sociedad Argentina de Biofísica; 2021

The study of many insecticidal compounds includes the knowledge of their interactionwith a specific receptor protein under the ligand-receptor model. However, consideringmembrane receptors and mainly to lipophilic ligands, this interaction can be non-specifically modulated by changes in the physical properties of the membrane, due to theactivity of these same products on the surrounding lipid molecules modulating thesupramolecular organization of the receptor environment. The objective of this work is todescribe how the lipophilic gabaergic insecticide Fluralaner affects the biophysicalproperties of DPPC Langmuir monolayers used as model membranes. We analyzed theseeffects by experimental and in silico complementary approaches. Experimentalpenetration isotherms indicated that the Fluralaner can be absorbed into the monolayer.Langmuir compression isotherms showed that Fluralaner molecules produce an expansionin the DPPC isotherm, by acting as spacers between the phospholipids. Also, the partitionof Fluralaner molecules into the lipidic phase affects the characteristic DPPC phasetransition, making it occur at higher surface pressure values. To provide a molecularinsight into the behavior of the system, we performed ALL ATOM detail MolecularDynamics simulations of DPPC monolayers in the presence of Fluralaner at differentmolecular packing states of the phospholipid. We were able to determine the probabledistribution of Fluralaner at different regions of the DPPC monolayer and to observe anexpansion of the simulated DPPC compression isotherm in the presence of Fluralaner, asobserved experimentally. We are currently performing a series of umbrella samplingsimulations to compute the potential of mean force (PMF).This will allow us to gain athermodynamic insight on the partition of the insecticide into the lipidic phase.