In this work, we combined MD simulations and continuum mechanics to study how Ca 2+ ions inluence the microscopic properties and macroscopic deformation of lipid membranes composed of POPC and POPS. We found that both the structure and luidity of the lipid membranes were signiicantly affected by the presence of Ca 2+ ions. A gradient of Ca 2+ across the lipid bilayer could create imbalanced stress in the two lealets, with the negatively charged lealet on the Ca 2+ -rich side becoming more condensed, thus inducing membrane curvature that bent the membrane away from the Ca 2+ -rich side. For a spherical vesicle, the asymmetric distribution of Ca 2+ on the two sides of the membrane could deform the vesicle into a locally or a globally multi-spherical shape in which a number of spheres are connected with ininitesimal necks. These results are summarized in Fig. , which can help clarify the question about the controversial membrane curvature caused by Ca 2+ and may lead to new methods for manipulating the membrane curvature of vesicles in chemical, biological, and nanosystems. 5 Materials and Methods