The protein kinase C alpha (PKC alpha) enzyme is a member of a broad family of serine/threonine kinases, which are involved in varied cellular signaling pathways. The initial step of PKCa activation involves the C2 subunit docking with the cell membrane, which is followed by interactions of the Cl domains with diacylglycerol (DAG) in the membrane. Notably, the molecular mechanisms of these interactions remain poorly understood, especially what effects, if any, DAG may have on the initial C2 docking. To further understand this process, we have performed a series of conventional molecular dynamics simulations to systematically investigate the interaction between PKC alpha-C2 domains and lipid bilayers with different compositions to examine the effects of POPS, PIP2, and 1-palmitoy1-2-oleoyl-sn-glycerol (POG) on domain docking. Our results show that the PKCa-C2 domain does not interact with the bilayer surface in the absence of POPS and PIP2. In contrast, the inclusion of POPS and PIP2 to the bilayer resulted in strong domain docking in both perpendicular and parallel orientations, whereas the further inclusion of POG resulted in only parallel domain docking. In addition, lysine residues in the C2 domain formed hydrogen bonds with PIP2 molecule bilayers containing POG. These effects were further explored with umbrella sampling calculations to estimate the free energy of domain docking to the lipid bilayer in the presence of one or two PIP2 molecules. The results show that the binding of one or two PIP2 molecules is thermodynamically favorable, although stronger in bilayers lacking POG. However, in POG-containing bilayers, the binding mode of the C2 domain appears to be more flexible, which may have implications for activation of full-length PKC alpha. Together, our results shed new insights into the process of C2 bilayer binding and suggest new mechanisms for the roles of different phospholipids in the activation process of PKC alpha.