Mechanistic Insight on Ethanol Driven Swelling and Disruption of Cholesterol Containing Biomimetic Vesicles From Coarse-Grained Molecular Dynamics

Shobhna and A Dutta and HK Kashyap, JOURNAL OF COMPUTATIONAL CHEMISTRY, 46, e70050 (2025).

DOI: 10.1002/jcc.70050

We have performed coarse-grained (CG) molecular dynamics (MD) simulations to delineate the impact of ethanol (EtOH) on cholesterol (CHOL) containing biomimetic bilayer and vesicle composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids. We have first deduced the missing interaction parameters for the POPC-CHOL-EtOH- water system within the SPICA/SDK CG force-field (CG-FF). By monitoring the electron density profiles, the orientational order parameter, and reproducing the all-atom MD-derived free energy for the insertion of ethanol from the bulk aqueous phase to the hydrophobic core of the POPC- CHOL lipid bilayer, we successfully determined all the missing non- bonding interaction parameters for the POPC-CHOL-EtOH-water system. The proposed force field was applied to investigate the effect of ethanol at various concentrations on unilamellar vesicles composed of POPC and cholesterol. It was found that 40 mol% or more concentration of ethanol is required to disintegrate or rupture the POPC-CHOL vesicle membranes. While cholesterol offers some resilience against the detrimental effects of ethanol, we still observe an increase in vesicle size (swelling) and a contraction in the bilayer thickness (thinning) as ethanol concentration rises from 0 to 30 mol%. At ethanol concentrations exceeding 30 mol%, the vesicles become increasingly susceptible to disintegration due to enhanced penetration of ethanol and water molecules into the hydrophobic core of the membranes.

Return to Publications page