Bilayer Membranes with Frequent Flip-Flops Have Tensionless Leaflets

[Image: see text] Biomembranes are built up from lipid bilayers with two leaflets that typically differ in their lipid composition. Each lipid molecule stays within one leaflet of the bilayer before it undergoes a transition, or flip-flop, to the other leaflet. The corresponding flip-flop times are very different for different lipid species and vary over several orders of magnitude. Here, we use molecular dynamics simulations to elucidate the consequences of this separation of time scales for compositionally asymmetric bilayers. We first study bilayers with two lipid components that do not undergo flip-flops on the accessible time scales. In such a situation, one must distinguish a bilayer state in which both leaflets have the same preferred area from another state in which each leaflet is tensionless. However, when we add a third lipid component that undergoes frequent flip-flops, the bilayer relaxes toward the state with tensionless leaflets, not to the state with equal preferred leaflet areas. Furthermore, we show that bilayers with compositional asymmetry acquire a significant spontaneous curvature even if both leaflets are tensionless. Our results can be extended to lipid bilayers with a large number of lipid components provided at least one of these components undergoes frequent flip-flops. For cellular membranes containing lipid pumps, the leaflet tensions also depend on the rates of protein-induced flip-flops.