Divalent cations bind to phosphoinositides to induce ion and isomer specific propensities for nano-cluster initiation in bilayer membranes

We report all-atom molecular dynamics simulations of physiologically composed asymmetric bilayers containing phosphoinositides in the presence of monovalent and divalent cations. We have characterized the molecular mechanism by which these divalent cations interact with phosphoinositides. Calcium desolvates more readily, consistent with single-molecule calculations, and forms a network of ionic-like bonds that serve as a "molecular glue'' that allows a single ion to coordinate with up to three phosphatidylinositol-(4,5)-bisphosphate lipids. The phosphatidylinositol-(3,5)-bisphosphate isomer shows no such effect and neither does PI(4,5)P2 in the presence of Mg. The resulting network of Ca-mediated lipid-lipid bonds grows to span the entire simulation space and therefore has implications for the lateral distribution of phosophoinositides in the bilayer. We observe context-specific differences in lipid diffusion rates, lipid surface densities, and bilayer structure. The molecular-scale delineation of ion-lipid arrangements reported here provides insight into similar nanocluster formation induced by peripheral proteins to regulate the formation of functional signaling complexes on the membrane.

Methods
GROMACS: we included the setup files