Ca-dependent membrane-binding by the Annexin A2/p11 heterotetramer (A2t) plays an important role in various biological processes including fibrinogen activation and exocytosis in neuroendocrine cells. Two models where A2t associates with a single membrane surface were generated and used to perform molecular dynamics simulations. The first model mimics initial A2t-membrane binding through both Annexin A2 (A2) subunits of A2t (TS model) while the second model mimics A2t-binding through a single A2 subunit (OS model). Conformational changes were summarized using principal component analysis (PCA), simulation snapshots, and distance plots from the simulations. The full TS model, including the p11 dimer, fully associates with the membrane adopting a stable structure with little conformational variation as evidence by PCA. The unassociated subunits of the OS model moved toward the membrane. The molecular mechanics/Generalized-Born surface area (MMGBSA) method was applied to investigate the energetics of the models. The MMGBSA results demonstrated that R63 of p11 was the primary contributor to the p11-membrane interaction. The TS model results were both consistent with those found in the literature and provide novel insights about the specific residues driving the A2t-membrane interaction. Additionally, it represents the most complete model of A2t on the membrane surface available.Communicated by Ramaswamy H. Sarma.