In silico Design and Analysis of Stability Parameters of Asymmetrical Liposomes

Abstract

Asymmetric liposomes are vesicles that can be assembled from different lipids compositions to improve specific characteristics for each leaflet of the liposome, depending on the intended use. However, the characterization of these nanosystems at an experimental level is complex. The use of MD simulations, and specifically CG models as the Martini force field, allows the design and analysis of these lipidic nanostructures to be faster and cheaper experimentally. Despite the innovation and constant development of MD simulations, this tool has not yet been used as a method to evaluate multiple lipid compositions for asymmetric liposomes, which led to this study, where the design and analysis of multiple asymmetric bilayers and vesicles containing DOTAP, DOPE, DSPC, and cholesterol were created through the INSANE and BUMPy scripts for further evaluation of their structure and stability by measuring their bilayer thicknesses, APL, SASA, gyration radius, and cholesterol positioning. All simulated structures remained stable for 3 microseconds and showed different behaviors depending on their composition, especially cholesterol content that strongly affected the structures' characteristics, meaning that the Martini CG model can be used to determine characteristics of interest in the analysis of multiple liposomal compositions. Based on the analysis made of the bilayers and vesicles during this work, bilayers’ compositions DOTMA:DOPE 1:1, DOTMA:DOPE:Cholesterol 1:1:1, and 5:3:0.4 had the best properties to remain stable over time, and vesicle’s composition DOTMA:DOPE:Cholesterol 1:1:1 presented more satisfactory results overall. Further analysis of the vesicle might be beneficial for a better understanding of the composition. The proposed work serves as a first approach to use MD simulations as a tool to be applied in the decision-making process for developing drug delivery carriers in experimental laboratories, reducing economic and time restrictions.