Comprehensive Speciation and Computational Study of Cu2+ and Zn2+ Complexation with O-Phosphorylethanolamine and O-Phosphorylcholine in Aqueous Solution

An extensive study on the interactions between O-phosphorylethanolamine (PEA) and O-phosphorylcholine (PPC), Cu2+ and Zn2+, is thoroughly described. The formation constants were determined at different temperatures (15 ≤ t/°C ≤ 37) and ionic strengths (0.15 ≤ I/mol L−1 ≤ 0.97) by potentiometric titrations. For the Zn2+-PEA/-PPC systems, speciation models were also confirmed by 1H NMR titrations at t = 25 °C and I = 0.15 mol L−1 in NaCl. Sequestering abilities were calculated under different temperatures and physiological conditions. Density Functional Theory (DFT) calculations along with enhanced sampling of the conformational space were performed aimed to better elucidate the Cu2+-, Zn2+- PEA/PPC molecular interactions and their relative stabilities. Overall, both experiments and computer simulations showed that the complex species involved in the Cu2+–PEA system exhibited a significant and selective stability, particularly in conditions simulating cerebrospinal fluid. While the binding molecular mechanisms were elucidated via DFT supplemented by automized conformational search, the computational binding energies trend qualitatively follows the experimental logK behavior across the Cu2+-, Zn2+- PEA/PPC complexes. These results highlight the potential physiological role of PEA in modulating free copper levels and regulating its redox activity in pathological conditions, such as Wilson’s Disease (WD).