Effect of calcium and magnesium on phosphatidylserine membranes: experiments and all-atomic simulations

It is known that phosphatidylserine (PS(-)) lipids have a very similar affinity for Ca(2+) and Mg(2+) cations, as revealed by electrokinetic and stability experiments. However, despite this similar affinity, experimental evidence shows that the presence of Ca(2+) or Mg(2+) induces very different aggregation behavior for PS(-) liposomes as characterized by their fractal dimensions. Also, turbidity measurements confirm substantial differences in aggregation behavior depending on the presence of Ca(2+) or Mg(2+) cations. These puzzling results suggest that although these two cations have a similar affinity for PS(-) lipids, they induce substantial structural differences in lipid bilayers containing each of these cations. In other words, these cations have strong ion-specific effects on the structure of PS(-) membranes. This interpretation is supported by all-atomic molecular-dynamics simulations showing that Ca(2+) and Mg(2+) cations have different binding sites and induce different membrane hydration. We show that although both ions are incorporated deep into the hydrophilic region of the membrane, they have different positions and configurations at the membrane. Absorbed Ca(2+) cations present a peak at a distance ~2 nm from the center of the lipid bilayer, and their most probable binding configuration involves two oxygen atoms from each of the charged moieties of the PS molecule (phosphate and carboxyl groups). In contrast, the distribution of absorbed Mg(2+) cations has two different peaks, located a few angstroms before and after the Ca(2+) peak. The most probable configurations (corresponding to these two peaks) involve binding to two oxygen atoms from carboxyl groups (the most superficial binding peak) or two oxygen atoms from phosphate groups (the most internal peak). Moreover, simulations also show differences in the hydration structure of the membrane: we obtained a hydration of 7.5 and 9 water molecules per lipid in simulations with Ca(2+) and Mg(2+), respectively.