Molecular dynamics modeling of pore stabilization and reorganization of lipid bilayers during electrotherapy

OJEDA PE; SUÁREZ C; FERNÁNDEZ ML

Rosario

Congreso; XIII Argentine Congress of Bioinformatics and Computational Biology. XIII International Conference of the Iberoamerican Society of Bioinformatics. III Annual Meeting of the Ibero-American Artificial Intelligence Network for Big BioData; 2023

Electrotherapies are a group of techniques that apply electric pulses to permeabilize the plasmamembrane in order to force the cell uptake of a nonpermeant cytotoxic agent (electrochemotherapy) or a gene of therapeutic interest (electrogene transfer); to induce apoptosis (irreversible electroporation); to facilitate the release from inside the cell of a product of commercial interest (food technology). All these processes are possible by inducing pores in the cell membrane. Based on bibliography we developed in silico two lipid bilayer models to mimic the normal and tumor cell membranes by varying the lipid composition. Both models are composed by: cholesterol (CHOL), dioleoilphosphatidyletanolamine (DOPE), dioleoilphosphatidylserine (DOPS), dioleoilphosphatidylcholine (DOPC) and sphingomyelin (SM). While in tumor bilayer systems both leaflets have identical lipid composition, normal bilayer systems present different lipid proportions in each leaflet. By molecular dynamics simulations, the membrane models were exposed to a high electric field normal to the bilayer, applied in one of the two possible directions, to open a single pore.The porated configuration obtained is then exposed to a lower electric field, in the same direction, to keep the pore open for 100 ns. Membrane response to the sustained electric field was evaluated considering: lipid redistribution between bilayer leaflets; pore stability, size and lipid composition; and ion passage through the pore. Obtained results indicate that: 1) The electric field range appropriate to keep the pore open is very narrow (0.050 +/- 0.001 V/nm). 2) The pore structure remains constant after 100 ns considering both lipid composition and final pore size, for both types of membrane models and electric field directions. 3) The tumor bilayer response to the electric field is different from the normal bilayer, being the last one also dependent on the field direction. 4) Pore stability is related to DOPS translocation. 5) The velocity of ion passage through the pore depends on the pore size up to a maximum. These results suggest that the response of the tumor cell would be different from the normal one during an electrotherapy.