The C2 domain is an important membrane binding motif in cell signaling pathways found ubiquitously in mammals. Two synaptotagmin (Syt) proteins, Syt1 and Syt7, each employ two C2 domains (C2A and C2B) to interact with membranes during exocytosis, acting as Ca2+-sensors. To explore Ca2+ ion binding and membrane association of the Syt1 and Syt7 C2 domains, we performed molecular dynamics simulations on a series of model systems. First, in the solvated proteins simulations, we found that Ca2+ ions were chelated by the protein oxygen atoms in the Ca2+-binding loops (CBLs): the side chain oxygen atoms in the aspartate and the serine residues, and backbone oxygen atoms. However, the number of bound Ca2+ ions and their coordination shell compositions varied. Syt1 C2A and Syt7 C2A and C2B each bound 3 Ca2+ ions tightly, but Syt1 C2B only bound 2 Ca2+ ions tightly and the outermost Ca2+ ion weakly. Water molecules and Cl-- ions were also recruited from the bulk solution to complete the Ca2+ solvation shells. Two chimeric C2 domains (Syt7:1C2ACH and Syt1:7C2BCH) were also studied as comparisons with the wild-type proteins. Syt7:1C2ACH is a hybrid of the Syt7 C2A body and the Syt1 C2A CBLs, whereas Syt1:7C2BCH the Syt1 C2B body and the Syt7 C2B CBLs. Our data suggests that Syt7:1C2ACH shows similar Ca2+-binding to the wild-type C2A of Syt1 and Syt7. In contrast, the Ca2+ ion binding of Syt1:7C2BCH resembles Syt1 C2B in agreement with experiment. Second, we generated four of Syt7 C2A to 3:1 POPC/POPS membrane associated models. F229 in CBL3 inserted deep into the membrane shortly after the beginning of the simulations, on the other hand, F167 in CBL1 entered and left the membrane constantly. We suspect that this oscillating motion is caused by the competition between the electrostatic attractions (between the polybasic region near the beta4 strand and lipid head groups) and hydrophobic interactions (between F167 and the lipid acyl chains). We conclude that the affinity of the two Syt isoforms for Ca2+ ions is important predictor of the Syt-mediated membrane fusion.