Two mechanisms of permeation of small neutral molecules and hydrated ions across phospholipid bilayers

Abstract The Gibbs free energy of dipole or iron permeation of lipid bilayers is calculated as the sum of all electrostatic, solvophobic and specific interactions. Partitioning models are consistent with dipole permeation and some features of ionic permeation, particularly if the solvophobic energy is taken into account. Ionic and dipole permeabilities are extremely sensitive to the ionic/dipolar radius. Despite this sensitivity, calculations of the permeability can be carried out for typical monovalent cations, and provide reasonable estimates, but only for hydrated species. An alternative mechanism proposed for ionic permeation involves the occurrence of transient pore-like defects in lipid bilayers which permit ions to bypass the Born energy barrier. The two alternative hypothesis, partitioning vs. transient pores, can be tested by measuring the ionic and dipolar permeation through bilayers of varying thickness. Experimental observations for both potassium and proton permeability are consistent with the transient pore mechanism for shorter chain lipids, but tend towards the theoretical line for partitioning models for longer chain lipids. Results for small neutral solutes are best explained by the solubility-diffusion mechanism. The proposed method of calculation of the Gibbs free energy of ion or dipole membrane transfer and the liquid membrane permittivity can be effectively used not only in describing the biophysical properties of membranes, but also in extraction processes, pharmaceutical applications and liquid membrane separations.