What Is the Preferred Conformation of Phosphatidylserine–Copper(II) Complexes? A Combined Theoretical and Experimental Investigation

Phosphatidylserine (PS) has previously been found to bind Cu²⁺ in a ratio of 1 Cu²⁺ ion per 2 PS lipids to form a complex with an apparent dissociation constant that can be as low as picomolar. While the affinity of Cu²⁺ for lipid membranes containing PS lipids has been well characterized, the structural details of the Cu–PS₂ complex have not yet been reported. Coordinating to one amine and one carboxylate moiety on two separate PS lipids, the Cu–PS₂ complex is unique among ion–lipid complexes in its ability to adopt both <i>cis</i> and <i>trans</i> conformations. Herein, we determine which stereoisomer of the Cu–PS₂ complex is favored in lipid bilayers using density functional theory calculations and electron paramagnetic resonance experiments. It was determined that a conformation in which the nitrogen centers are <i>cis</i> to each other is the preferred binding geometry. This is in contrast to the complex formed when two glycine molecules bind to Cu²⁺ in bulk solution, where the <i>cis</i> and <i>trans</i> isomers exist in equilibrium, indicating that the lipid environment has a significant steric effect on the Cu²⁺ binding conformation. These findings are relevant for understanding lipid oxidation caused by Cu²⁺ binding to lipid membrane surfaces and will help us understand how ion binding to lipid membranes can affect their physical properties