Our long term goal is to create a model of the prothrombinase complex. We have recently proposed a complete model in solution of human coagulation factor Va (pdb entry 1y61). In the present study we create the framework needed to accomplish our final goal. We first created a lipid bilayer that mimics the cell membrane surface. The lipid bilayer mimetic was set up as a random mixture of 1-palmitoyl, 2-oleoyl phosphatidylcholine (POPC) and 1-palmitoyl-2-oleoyl-phosphatidylserine (POPS) using a 4:1 ratio. Human prothrombin fragment one is a highly homologous region among species, except zebrafish and hagfish ( Jagadeeswaran et al., Blood Cells Mol. Dis., 2000). In the absence of a crystal structure of the entire human prothrombin molecule, we created a homology model of human prothrombin fragment 1 (amino acid residues 1–155). In the homology modeling procedure we used three X-ray structures available for the bovine prothrombin fragment 1 molecule (Soriano-Garcia et al., Biochemistry, 1992, Seshadri et al., J. Mol. Biol., 1991, and Huang et al., Nat. Struct. Biol., 2003). One extra Ca2+ was added as proposed in an earlier human prothrombin fragment 1 homology model (Leping et al., Protein Sci., 1995). The modeling was performed using the Modeller software package. Prothrombin fragment 1 was then inserted into the lipid bilayer so the region composed of amino acid residues 1–10 were positioned in the hydrophobic core, whereas the γ-carboxyglutamic acid rich region was on the surface of the lipid bilayer as proposed (Falls et al., J. Biol. Chem., 2001). Molecular dynamics simulations on the 10 ns time scale of the prothrombin fragment 1 bound to the POPC/POPS lipid bilayer showed a conformational change in prothrombin fragment 1. This conformational change can be described as a rearrangement of three regions: region A (composed of amino acid residues 1–30), region B (composed of amino acid residues 31–69), and region C (composed of amino acid residues 70–155). Root mean square deviation (RMSD) of region A compared to the starting model was found to be 1.61 Å whereas for region C was found to be 1.91 Å. The RMSD of region B was found to be 1.99 Å. Because region B contains two α- helix motifs the deviation is due to the amino acids found at both ends (i.e., the ones that connect region A and region C with region B). During the simulations the initial Ca2+ ions positions were found to be preserved in the vicinity of the γ-carboxyglutamic amino acid residues. The secondary structure elements were preserved during simulations. Following a 10 ns simulation three γ-carboxyglutamic residues (7, 14 and 25) of prothrombin fragment 1 were found to form polar contacts with POPS molecules. Due to the conformational change, Asp55 was also found to interact with one POPS molecule. This amino acid residue was previously shown to be located near the active site of meizothrombin. Overall, our studies present for the first time a POPC/POPS lipid bilayer model, and show that in the presence of Ca2+ ions a conformational change occurs in prothrombin fragment 1 following its interaction with the lipid bilayer.