Microsecond MD simulations were carried out to study the effects of the mixtures of Ca(2+), Mg(2+), Na(+), and K(+) ions on a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) bilayer. It has been revealed that the binding efficiency of these ions with POPG lipids is in the following order, Ca(2+) > Mg(2+) > Na(+) > K(+). The binding free energy of Ca(2+) to the lipid bilayer is ~-4.0 kcal/mol, which is much lower than those of other ions. This result explains why the effects of the ion mixture on membranes are particularly sensitive to the concentration of calcium. The on-rates of different ions do not have a large difference, while the off-rate of Ca(2+) is 2-3 orders of magnitude smaller than those of the others. Therefore, the strongest binding affinity of Ca(2+) is mainly determined by its smallest off-rate. The structure of the lipid bilayer is influenced dominantly by the concentration of Ca(2+) ions.
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