Model studies of lipid flip-flop in membranes

Biomembranes, which are made of a lipid bilayer matrix where proteins are embedded or attached, constitute a physical barrier for cell and its internal organelles. With regard to the distribution of their molecular components, biomembranes are both laterally heterogeneous and transversally asymmetric, and because of this they are sites of vital biochemical activities. Lipids may translocate from one leaflet of the bilayer to the opposite either spontaneously or facilitated by proteins, hence they contribute to the regulation of membrane asymmetry on which cell functioning, differentiation, and growth heavily depend. Such transverse motion-commonly called flip-flop-has been studied both experimentally and computationally. Experimental investigations face difficulties related to time-scales and probe-induced membrane perturbation issues. Molecular dynamics simulations play an important role for the molecular-level understanding of flip-flop. In this review we present a summary of the state of the art of computational studies of spontaneous flip-flop of phospholipids, sterols and fatty acids. Also, we highlight critical issues and strategies that have been developed to solve them, and what remains to be solved.