Ion permeation across the membrane: A comprehensive comparison analysis on passive permeations of differently charged ions

Abstract

• The unassisted permeation of sulfide(-2 charge) in molecular details is explored. • The permeation of sulfide requires the coupling of cations, and causes little disturbance to the lipid bilayers. • The free energies of all ions and water, whether cation or anion, are highly correlated with the hydrophilic shell. • Membrane deformation, water wire or hydration can increase the energy barrier. Charge is very important for passive permeation of small molecules, but earlier research has led to different models of passive permeation of small molecules across lipid bilayer, which hardly achieved consistent and significant conclusions about the mechanism. Our previous molecular dynamics simulations on the transmembrane passive permeations of sodium, potassium, chloride and calcium ions had suggested molecular charge as one of the key factors in this process. Here we put more pieces into this puzzle by simulations on water (neutral) and sulfide (with two negative charges) molecules. The permeation profiles and free energies of all the ions mentioned above are comprehensively compared and analyzed, where the permeability coefficients calculated from this simulation are quite consistent with those from experiments. The permeation process of water is very simple, causing almost no perturbation to the lipid bilayers and fully conforming to the solubility-diffusion model, and the free energy barrier is very low. The permeation of sulfide needs to be accompanied by two sodium ions to offset its charges, and there is also little disturbance to the lipid bilayers. Based on the current study and comparison with previous ones, it is found that membrane deformation, water wire or hydration can increase the energy barrier. Specifically, the free energy of cation is more related to membrane deformation and water wire, while the free energy of anion is more related to hydration. More importantly, if the number of all oxygens including lipid oxygens and water oxygens within 0.5 nm of the ion is considered as an indicator of the “hydrophilic shell”, the free energies of all ions and water, whether cation or anion, are highly correlated with the hydrophilic shell. Hydrophilic shell is possible to be a valuable indicator that can be applied not only to ions, but also to molecules and even macromolecules due to its ubiquitous presence in the transmembrane permeation process of all substances.