Bending the rules: Molecular dynamics of hydroxylated sphingolipid membranes with 2-hydroxyoleic acid

In this study, we introduce a novel method for quantifying the mechanical properties of lipid membranes-bending rigidity (κ), Gaussian rigidity (κG), and surface tension (γ) using molecular dynamics (MD) simulations. Our approach is applied to membranes incorporating 2-hydroxyoleic acid (2OHOA), a synthetic oleic acid derivative currently under clinical investigation for its anticancer properties. 2OHOA modifies the plasma membrane composition in cancer cells and activates sphingomyelin synthase 1 (SMS1), an enzyme critical for maintaining sphingolipid levels in the plasma membrane. This research focuses on how the integration of 2OHOA into ceramide and sphingomyelin alters the mechanical and biophysical properties of these membranes. We employed MD simulations to analyze structural parameters such as lipid area, volume, and bilayer thickness. Additionally, by constructing a system of linear equations based on the Helfrich-Seifert model, we estimated the mechanical properties of hydroxylated versus non-hydroxylated membranes. Our findings reveal significant membrane rigidity and curvature changes due to hydroxylation, affecting membrane-protein interactions and cellular processes like vesiculation. This work provides critical insights into the molecular mechanisms by which hydroxylation influences membrane elasticity, with implications for both fundamental biophysics and therapeutic applications in cancer treatment.