Calcium-Lipid Interactions Observed with Isotope-Edited Infrared Spectroscopy

Calcium ions bind to lipid membranes containing anionic lipids; however, characterizing the specific ion-lipid interactions in multicomponent membranes has remained challenging because it requires nonperturbative lipid-specific probes. Here, using a combination of isotope-edited infrared spectroscopy and molecular dynamics simulations, we characterize the effects of a physiologically relevant (2 mM) Ca2+ concentration on zwitterionic phosphatidylcholine and anionic phosphatidylserine lipids in mixed lipid membranes. We show that Ca2+ alters hydrogen bonding between water and lipid headgroups by forming a coordination complex involving the lipid headgroups and water. These interactions distort interfacial water orientations and prevent hydrogen bonding with lipid ester carbonyls. We demonstrate, experimentally, that these effects are more pronounced for the anionic phosphatidylserine lipids than for zwitterionic phosphatidylcholine lipids in the same membrane. SIGNIFICANCE Phosphatidylserines (PS) play an active role in signaling processes. In some of these roles, proteins recognize and bind PS through bridging calcium ions, but the specific role of the lipid headgroups in mediating these interactions is not understood. Studies using a variety of biophysical techniques have also indicated that interactions between PS and calcium can reshape the structural and mechanical properties of lipid membranes. However, these interactions are not as well characterized in more complex membranes containing multiple lipid components. Here, we have used isotope-edited infrared spectroscopy to nonperturbatively characterize the effect of physiological concentrations of calcium on membranes containing a mixture of PS and the more abundant phosphatidylcholines.