Membrane-Ion Interactions Modify the Lipid Flip-Flop Dynamics of Biological Membranes: A Molecular Dynamics Study

The asymmetric distribution of lipids in the cell membrane is maintained by protein transporters, and in the absence of proteins, by spontaneous flip-flop of lipids that involve the formation of transient pores in the membrane. The composition of the cell membranes influences the metabolism of the cell by modulating the function of transmembrane proteins, and flip-flop processes are therefore of key importance. Membranes are in direct contact with aqueous solutions, containing ions of different compositions that interact with the lipid head groups or cross the cell membrane through transmembrane channels. The impact of the ions on the lipid flip-flop rates is, however, an outstanding question. Here, we show that the flip-flop rate slows down significantly with the increasing valence of the cation, from minutes for monovalent cations (Na⁺, K⁺) to hours for divalent (Mg²⁺, Ca²⁺) or days for trivalent cations (Yb³⁺).