Spontaneous Lipid Flip-Flop in Membranes: A Still Unsettled Picture from Experiments and Simulations

Biomembrane asymmetry, whose regulation is important for function, is maintained by the movement of lipids from one bilayer leaflet to the other (flip- flop). During the last decades a number of studies have been done to characterize this process, and it was found that it can be spontaneous or assisted by protein transporters. It can be accelerated or inhibited by various factors, e.g., it can be induced by mechanical stresses. It was also found that flip-flop rate and mechanism strongly depend on the molecular structure of the flipping lipid and on the composition and physical state of the membrane. Yet, large discrepancies exist among the data available in the literature, and a quantitative and comprehensive understanding of this process is still missing. This chapter reviews our current knowledge of the molecular aspects of spontaneous (or passive) flip-flop. An overview of experimental studies is presented, together with a summary of the state of the art of computer simulation studies, which enable a direct insight at the molecular level. The achievements and limitations of experimental and computational approaches are pointed out, as well as the challenges that remain to be addressed.