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

The specificity of anionic phospholipids-calcium ion interaction and lipid demixing has been established as a key regulatory mechanism in several cellular signaling processes. The mechanism and implications of this calcium-assisted demixing have not been elucidated from a microscopic point of view. Here, we present an overview of atomic interactions between calcium and phospholipids that can drive nonideal mixing of lipid molecules in a model lipid bilayer composed of zwitterionic (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)) and anionic (1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine (POPS)) lipids with computer simulations at multiple resolutions. Lipid nanodomain formation and growth were driven by calcium-enabled lipid bridging of the charged phosphatidylserine (PS) headgroups, which were favored against inter-POPS dipole interactions. Consistent with several experimental studies of calcium-associated membrane sculpting, our analyses also suggest modifications in local membrane curvature and cross-leaflet couplings as a response to such induced 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 calcium ion's impact on membrane biophysics.