Local accumulation of diacylglycerol alters membrane properties nonlinearly due to its transbilayer activity

Diacylglycerols (DAGs) are bioactive lipids that are ubiquitously present at low concentrations in cellular membranes. Upon the activation of lipid remodeling enzymes such as phospholipase C and phosphatidic acid phosphatase, DAG concentration increases, leading to a disruption of the lamellar phase of lipid membranes. To investigate the structural origin of these phenomena, here we develop a coarse-grained model for DAGs that is able to correctly reproduce its physicochemical properties, including interfacial tension and flip-flop rate. We find that even at low concentrations a nonnegligible percentage of DAG molecules occupies the interleaflet space. At high concentrations, DAG molecules undergo a phase-separation process from lamellar lipids, segregating in DAG-only blisters and effectively reducing the DAG surface pool available to peripheral enzymes. Our results allow for a better understanding of the role of DAGs in cellular membranes and provide a new tool for the quantitative estimation of low-abundance lipids on membrane properties.