Coarse Grained Molecular Dynamics Simulation of the Interaction of Cytochrome C with Lipid Bilayers

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In addition to a well-characterized role of cytochrome c (cyt c) as a pro-apoptotic factor acting after its release from mitochondria into the cytosol, a new pro-apoptotic function of the intra-mitochondrial pool of cyt c has been recently identified. Early in apoptosis, cyt c interacts with a mitochondria-unique phospholipid, cardiolipin (CL), that massively transmigrates from the inner to the outer mitochondrial membrane. In the complexes thus formed, cyt c becomes a peroxidase which catalyzes peroxidation of polyunsaturated CL species into products that are required for the execution of the apoptotic program. The essential details of the cyt c/CL interactions - leading to the gain of cyt c's peroxidase competence towards CL - remain to be elucidated. Here, we used Coarse Graining Molecular Dynamic (CG-MD) simulation as a computational route to explore structural details of cyt c interactions with CL-containing phospholipid bilayer. using the MARTINI force field of a 4-to-1 atoms-to-bead mapping for both lipids and protein, we simulated a lipid bilayer containing 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 20% tetraoleoyl-CL (TOCL). Furthermore, we investigated the effect of CL peroxidation on membrane structure and interactions with cyt c. The simulation visualizes cyt c movement toward the phospholipid bilayer, to which it binds and then migrates along its surface. Inside the bilayer, clustering of CL with respect to the position of cyt c on the bilayer surface was observed. Peroxidation of CL altered the phospholipid membrane and caused the appearance of disorganized domains. Furthermore, increasing levels of peroxidation resulted in decreasing capacity of cyt c to interact with the membrane, whereby cyt c completely lost the ability to bind to the bilayer containing fully peroxidized CL (with all four of CL's acyls oxidiatively modified). Supported by NIH grant R01 ES020693.