Fibroblast Growth Factors 2 (FGF2) belongs to a 23 member family of growth factors, important for physiological processes such as embryonic development, tissue regeneration, wound repair hematopoiesis and also plays critical role under pathophysiological conditions. Unlike other FGF family members, FGF2 lacks signal peptide and is transported into the extracellular space by an ER/Golgi-independent mechanism. Cell-based and biochemical in vitro studies have indicated an unconventional direct translocation of FGF2 across the plasma membrane. The translocation process is dependent on sequential interactions of FGF2 with the phosphoinositide PI(4,5)P2, which triggers aggregation of FGF2 on the membrane surface. Using molecular dynamics (MD) simulations, we shed light on the initial molecular events leading to the translocation process which begins with the binding of FGF2 monomer with PI(4,5)P2. Further, our simulations predict high- affinity orientation for FGF2 which favours dimerization through Cys95-Cys95 disulfide bridge and the results are consistent with the biochemical and structural experiments. The findings establish both the molecular basis and the minimal molecular machinery required for unconventional secretion of FGF2 from cells that consists of a surprisingly simple set of factors.