Dehydration Energy Regulates the Binding Affinity of Divalent Cations to Lipid Bilayers

The interaction between cell membranes and metal ions plays a crucial role in numerous physiological processes, yet the underlying molecular mechanisms remain incompletely understood. Using a neutral 1,2-dipalmitoyl- sn -glycero-3-phosphocholine (DPPC) lipid bilayer as a model system, we combined sum frequency generation vibrational spectroscopy (SFG-VS) and attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) to investigate the interactions of Mg 2+, Zn 2+, and Cu 2+ with the bilayer. Our results demonstrate that ion binding disrupts the structural symmetry of lipid tails, following the binding affinity of the order Cu 2+ > Zn 2+ > Mg 2+ . The binding sites are highly specific: Cu 2+ binds exclusively to the phosphate groups, Zn 2+ interacts with both phosphate and glycerol moieties, while Mg 2+ binds weakly to DPPC, inducing only minor structural perturbations in the headgroup and tail regions. Ion binding substantially enhances the hydration of the lipid bilayer, leading to an increase in SFG signals that scales with the binding affinity of the ions. Analysis of the bend+libration combination band of ion hydration shells using ATR-FTIR reveals that their hydration structures differ markedly. Water molecules in the hydration shell of Cu 2+ exhibit greater lability and lower dehydration energy, whereas Zn 2+ and Mg 2+ display stronger ion–water interactions and higher dehydration energies (Mg 2+ > Zn 2+ > Cu 2+ ). These intrinsic differences in hydration free energy likely contribute significantly to the distinct binding affinities of the ions for lipid membranes. These findings offer critical mechanistic insights into cation–membrane interactions in biological systems.