Abstract

Lipid droplets (LDs) are essential organelles for cellular energy homeostasis, and their fusion is a critical process for regulating LD size and metabolism. This fusion event is fundamentally a membrane-remodeling process, initiated by the formation of a hemifusion intermediate known as a stalk. The present study investigates the biophysical mechanism of LD fusion by focusing on the **energy barrier** associated with the formation of the **monolayer stalk** intermediate. Using a theoretical framework based on continuum membrane elasticity and molecular dynamics simulations, we quantify the free energy landscape of the initial hemifusion step. Our results reveal that the energy barrier is significantly influenced by the spontaneous curvature of the lipid monolayer, the line tension at the LD surface, and the hydration forces between the approaching membranes. Specifically, we demonstrate that a high positive spontaneous curvature dramatically lowers the energy barrier, suggesting a key role for specific lipid compositions or protein-induced curvature in facilitating fusion. The calculated energy barrier provides a quantitative measure for the kinetic rate of LD fusion, offering new insights into the regulation of LD dynamics in health and disease. This work establishes a critical link between the molecular properties of the LD surface and the macroscopic process of organelle fusion.