Kinetic and thermodynamic aspects of lipid translocation in biological membranes

A theoretical analysis of the lipid translocation in cellular bilayer membr anes is presented. We focus on an integrative model of active and passive t ransport processes determining the asymmetrical distribution of the major l ipid components between the monolayers. The active translocation of the ami nophospholipids phosphatidylserine and phosphatidylethanolamine is mathemat ically described by kinetic equations resulting from a realistic ATP-depend ent transport mechanism. Concerning the passive transport of the aminophosp holipids as well as of phosphatidylcholine, sphingomyelin, and cholesterol, two different approaches are used. The first treatment makes use of thermo dynamic flux-force relationships. Relevant forces are transversal concentra tion differences of the lipids as well as differences in the mechanical sta tes of the monolayers due to lateral compressions. Both forces, originating primarily from the operation of an aminophospholipid translocase, are expr essed as functions of the lipid compositions of the two monolayers. In the case of mechanical forces, lipid-specific parameters such as different mole cular surface areas and compression force constants are taken into account. Using invariance principles, it is shown how the phenomenological coeffici ents depend on the total lipid amounts. In a second approach; passive trans port is analyzed in terms of kinetic mechanisms of carrier-mediated translo cation, where mechanical effects are incorporated into the translocation ra te constants. The thermodynamic as well as the kinetic approach are applied to simulate the time-dependent redistribution of the lipid components in h uman red blood cells. In the thermodynamic model the steady-state asymmetri cal lipid distribution of erythrocyte membranes is simulated well under cer tain parameter restrictions: 1) the time scales of uncoupled passive transb ilayer movement must be different among the lipid species; 2) positive cros s-couplings of the passive lipid fluxes are needed, which, however, may be chosen lipid-unspecifically. A comparison of the thermodynamic and the kine tic approaches reveals that antiport mechanisms for passive lipid movements may be excluded. Simulations with kinetic symport mechanisms are in qualit ative agreement with experimental data but show discrepancies in the asymme trical distribution for sphingomyelin.