Molecular insights into sphingomyelin membrane alterations induced by very long-chain lysophospholipids

Hypothesis Lipid membrane structure and mechanics are shaped by the molecular geometry and interactions of their amphiphiles. Very long-chain lysophosphatidylcholines (VLC-LysoPCs), with extended hydrophobic tails, insert into bilayers and perturb packing across leaflets. The VLC-LysoPCs 1-tetracosanoyl- (C24) and 1-hexacosanoyl- (C26) differ in chain length and insertion depth, and are thus expected to differentially modulate bilayer structure and mechanics. When co-incorporated, their distinct insertion depths and conformational behaviors may act cooperatively to reorganize lipid packing and modulate interleaflet coupling in ways unattainable by either species individually. Such synergy may underlie membrane remodeling during pathological VLC-lipid accumulation and offer design principles for synthetic membranes with tunable mechanics. Simulations Atomistic molecular dynamics simulations were performed on sphingomyelin bilayers containing either C24- or C26-LysoPCs, or both co-incorporated. Free energy calculations revealed the insertion mechanisms and thermodynamic profiles of each species. Structural remodeling, conformational dynamics, lipid diffusion, and interleaflet friction were evaluated through equilibrium and non-equilibrium simulations. Findings The insertion free energy of VLC-LysoPCs decreases when both C24 and C26 species are co-present in the sphingomyelin bilayer, indicating a thermodynamically cooperative effect that lowers the energetic cost of further incorporation. While C26 promotes extension of C24, C24 dampens the extension of C26, resulting in mutually modulated conformations that affect membrane packing and facilitate further incorporation. These changes reduced sphingomyelin mobility and decouple membrane leaflets. This is the first report to show that mixtures of VLC-LysoPCs with different chain lengths can cooperatively reshape membrane architecture and mechanics, offering design principles for tailored lipid-based membranes.