The study shows that cholesterol makes the fatty‑acid chains in cell‑like membranes pack tighter, but its effect on how hard it is to poke a hole through the membrane and how quickly vesicles fuse depends on the membrane’s composition. In simple POPC membranes cholesterol makes the membrane stronger, while in more complex mixtures that mimic synaptic vesicles it actually makes the membrane easier to break and speeds up fusion.

Cholesterol is a major determinant of biological lipid membrane properties. Its physiological levels are affected by widely used prescription drugs. The effect of changing the cholesterol content has been extensively studied in model lipid bilayers, but it still remains a matter of debate. Here we compare the effect of cholesterol on synaptic vesicle-mimicking (consisting of POPE, POPC, POPS) and single-component bilayers (containing POPC). We quantify the effects of cholesterol on the mechanical properties of the membrane (e.g., lipid packing, polarity, and the force needed for an AFM tip to break through the bilayer), and their relationship to membrane fusion. Cholesterol increases lipid chain packing both in PC/PE/PS and in POPC. However, in PC/PE/PS, contrary to POPC, cholesterol decreases the breakthrough force and accelerates spontaneous vesicle fusion. So, cholesterol may drive the properties of specific biological membranes in a direction that is opposite to that observed for simpler bilayers.