Calcium Ion Binding at the Lipid-Water Interface Alters the Ion Permeability of Phospholipid Bilayers

Calcium ions (Ca2+) play a fundamental role in membrane-associated physiological processes. Ca2+ can also significantly modulate the physicochemical properties of phospholipid bilayers, but whether this occurs at physiologically relevant concentrations is difficult to determine because of the uncertainty in the reported affinity of Ca2+ for phospholipid bilayers. In this article, we determine the apparent affinity of Ca2+ for zwitterionic phospholipid bilayers using tethered bilayer lipid membranes (tBLMs) used in conjunction with swept-frequency electrical impedance spectroscopy (EIS). We report that Ca2+ binds to phospholipid bilayers at physiologically relevant concentrations and modulates membrane permeability. We present direct experimental evidence that this effect is governed by specific interactions with select lipid headgroup moieties, which is supported by data from molecular dynamics simulations. This is the first reported use of tBLM/EIS to estimate cation-membrane affinity. Combined with MD simulations, this technique provides a novel methodology to elucidate the molecular details of cation-membrane interactions at the water-phospholipid interface.

Automated summary

In this study, the apparent affinity of Ca2+ for zwitterionic phospholipid bilayers was determined using tBLMs and EIS, showing that Ca2+ binds to phospholipid bilayers at physiologically relevant concentrations and modulates membrane permeability. Specific interactions with select lipid headgroup moieties were found to govern this effect, as supported by molecular dynamics simulations. This novel methodology provides a way to elucidate the molecular details of cation-membrane interactions at the water-phospholipid interface.