Budding of Asymmetric Lipid Bilayers: Effects of Cholesterol, Anionic Lipid, and Electric Field

Membrane budding is vital for various cellular processes such as synaptic activity regulation, vesicle transport and release, and endocytosis/exocytosis. Although protein-mediated membrane budding has been extensively investigated, the effects of the lipid asymmetry of the two leaflets and the asymmetrically electrical environments of the cellular membrane on membrane budding remain elusive. In this work, using coarse-grained molecular dynamics simulations, we systematically investigate the impacts of lipid bilayer asymmetry and external electric fields mimicking the asymmetric membrane potential on the membrane budding. The results show that the differential stress induced by the asymmetric distribution of lipids in the two leaflets is a crucial factor for the membrane budding. The unidirectional flip of cholesterol induced by the membrane curvature and the asymmetric ion adsorption induced by the anionic lipids promote the budding process. Furthermore, the external electric field applied perpendicularly to the bilayer plane increases the transmembrane potential and produces an additional differential stress across the leaflets by imposing an asymmetric torque on the lipid headgroups in the two leaflets, facilitating the membrane budding. These findings offer insights into how the structural and the environmental asymmetry in natural cellular membranes influence membrane budding in cellular processes.