Thermodynamic Driving Forces for Divalent Cations Binding to Zwitterionic Phospholipid Membranes

We calculated the free energies for calcium, magnesium, and zinc ions binding to a zwitterionic phospholipid bilayer by using molecular dynamics simulations and the enhanced umbrella sampling technique. By decomposing the free energy into entropic and enthalpic contributions, we found that Ca²⁺ has the highest binding affinity and that the overall process is endothermic combined with a secondary exothermic process at higher ion concentrations. The relatively low dehydration free energy of Ca²⁺ allows it to release coordinated water upon binding to the membrane. The dehydrated Ca²⁺ further coordinates with lipids, resulting in a weaker influence on the water orientation and increased entropy. However, when sufficient Ca²⁺ ions are adsorbed, the concentrated cation layer induces a positive electrostatic field, which enhances the energy barrier for further ion binding and orients the adjacent water, resulting in decreased entropy. In contrast, binding of Mg²⁺ and Zn²⁺ is exothermic and less favored because they remain fully hydrated when interacting with lipids.