Vesicle exocytosis is a promising pathway for brain drug delivery through the blood-brain barrier to treat neurodegenerative diseases. In vesicle exocytosis, the membrane fusion process is initiated by the calcium sensor protein named synaptotagmin-like protein4-a (Slp4-a). Understanding conformational changes of Slp4-a during the prefusion stage of exocytosis will help to develop vesicle-based drug delivery to the brain. In this work, we use molecular dynamics (MD) simulations with a hybrid force field coupling united-atom protein model with MARTINI coarse-grained (CG) solvent to capture the conformational changes of Slp4-a during the prefusion stage. These hybrid coarse-grained simulations are more efficient than all-atom MD simulations and can capture protein interactions and conformational changes. Our simulation results show that the calcium ions play critical roles during the prefusion stage. Only one calcium ion can remain in each calcium-binding pocket of Slp4-a C2 domains. The C2B domain of calcium-unbound Slp4-a remains parallel to the endothelial membrane, while the C2B domain of calcium-bound Slp4-a rotates perpendicular to the endothelial membrane to approach the vesicular membrane. For the calcium-bound case, three Slp4-a proteins can effectively bend lipid membranes at the prefusion stage, which could later trigger lipid stalk between membranes. This work provides a better understanding how C2 domains of Slp4-a operate during vesicle exocytosis from an endothelial cell.