Molecular Mechanisms of Lipid Raft Disintegrated by Ceramides: A Dependence of Acyl Lengths, Concentrations, and GM1 Guiding

Lipid rafts are known as dynamic microcompartments in cell membranes implicated with cellular penetration and molecular recruitment. Its compact structure reduces membrane fluidity, thereby affecting drug permeability and distribution and represents an underlying mechanism for cancer cells to resist chemotherapy. Lipid exchange within lipid rafts has attracted increasing attention, and ceramide (CER) is a potential candidate for dismantling lipid rafts; however, the molecular details and dynamic mechanism remain unclear. This study employs high-throughput coarse-grained molecular dynamic simulations to elucidate the mechanisms of lipid raft disintegrated by CER in atom-nearly resolution. Our results reveal that CER-induced lipid raft disruption is associated with its acyl chain length, specifically favoring chains of 8 carbons (CER-C8), which interferes with the association between cholesterol and saturated phospholipids within the lipid raft. This interference leads to structural disorganization of the lipid raft and membrane homogeneity. Furthermore, lipid raft dissociation is concentration-dependent: compared to a CER/lipid ratio of 34/287, higher CER amounts (80 or 120) exert a more pronounced disruptive effect. It is noteworthy that ganglioside GM1 plays a critical role in the efficient adsorption of CER clusters to lipid raft, other than a membrane nonbound state. The findings of this study provide a theoretical basis for understanding the role of CERs in disease and elucidate the molecular mechanisms by which CER disrupts the lipid raft.