Theoretical calculations of the permeability of monensin-cation complexes in model bio-membranes

Monensin is one of the best-characterized ionophores; it functions in the electroneutral exchange of cations between the extracellular and cytoplasmic sides of cell membranes. The X-ray crystal structures of monensin in free acid form and in complex with Na(+), K(+) and Ag(+) are known and we have recently measured the diffusion rates of monensin in free acid form (Mo-H) and in complex with Na(+) (Mo-Na) and with K(+) (Mo-K) using laser pulse techniques. The results have shown that Mo-H diffuses across the membrane one order of magnitude faster than Mo-Na and two orders of magnitude faster than Mo-K. Here, we report calculations of the translocation free energy of these complexes across the membrane along the most favorable path, i.e. the lowest free energy path. The calculations show that the most favorable orientation of monensin is with its hydrophobic furanyl and pyranyl moieties in the hydrocarbon region of the membrane and the carboxyl group and the cation at the water-membrane interface. Further, the calculations show that Mo-H is likely to be inserted deeper than Mo-Na into the bilayer, and that the free energy barrier for transfer of Mo-H across the membrane is approximately 1 kcal/mol lower than for Mo-Na, in good agreement with our measurements. Our results show that the Mo-K complex is unlikely to diffuse across lipid bilayers in its X-ray crystal structure, in contrast to the Mo-H and Mo-Na complexes. Apparently, when diffusing across the membrane, the Mo-K complex assumes a different conformation and/or thinning defects in the bilayer lower significantly the free energy barrier for the process. The suitability of the model for treating the membrane association of small molecules is discussed in view of the successes and failures observed for the monensin system.