We report all-atom molecular dynamics simulations of physiologically composed asymmetric bilayers containing phosphoinositides in the presence of monovalent and divalent cations.We have identified the molecular mechanisms of cations interacting with phosphoinositides. Ion condensation drives a rearrangement of neighboring lipids to both overcome the steric obstacles posed by bulky head groups and generate lipid-lipid groupings necessary for higherorder clusters above chance, however this effect is only apparent when phosphatidylinositol-(4,5)-bisphosphate (PI(4, 5)P2) and Ca2+ are present. Ca2+ desolvates more easily, 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 PI(4, 5)P2 lipids. We find that the phosphatidylinositol-(3,5)-bisphosphate isomer shows no such effect and neither does PI(4, 5)P2 in the presence of Mg2+. We observe mild variations in the inter-lipid hydrogen bonding that do not seem to drive the ion-mediated rearrangements. However, macroscopic properties such as bilayer area and diffusion coefficients are influenced by context-specific nanocluster formation. The molecular-scale delineation of ion-lipid arrangements reported here can shed insight into similar nanocluster formation inducedby peripheral proteins to regulate the formation of functional signaling complexes on the membrane.