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 cis and trans 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 cis 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 cis and trans 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.