Microscopic Picture of Calcium-Assisted Lipid Demixing and Membrane Remodeling Using Multiscale Simulations

The specificity of anionic phospholipids–Ca²⁺ ion interaction and lipid demixing has been established as a key mechanism in several cellular signaling processes. The mechanism and implications of this Ca²⁺-assisted demixing have not been elucidated from a microscopic point of view. Here, we present an overview of atomic interactions between Ca²⁺ and lipids that can drive non ideal mixing of lipids in a model bilayer composed of zwitterionic (phosphatidylcholine - PC) and anionic (phosphatidylserine - PS) lipids with computer simulations at multiple resolutions. Lipid nanodomain formation and growth were driven by Ca²⁺-enabled lipid bridging of the charged PS headgroups, which were favored against inter-PS dipole interactions. Consistent with several experimental studies of Ca²⁺-associated membrane sculpting, our analyses also suggest modifications in local membrane curvature and cross-leaflet couplings as a response to such lateral heterogeneity. In addition, reverse mapping to a complementary atomistic description revealed structural insights in the presence of anionic nanodomains, at timescales not accessed by previous computational studies. This work bridges information across multiple scales to reveal a mechanistic picture of Ca²⁺ ion’s impact on membrane biophysics.