Cytochrome P450 (P450) enzymes are components of a mixed-function oxidase system located in the membrane of endoplasmic reticulum. Using multiscale computational methods, we investigated the structure and dynamics of the full-length membrane-anchored P450 1A2 enzymes. The absence of the structural information on the trans-membrane (TM) domain of these two proteins was surpassed by employing a spontaneous self-assembly molecular dynamics (MD). The simulation was performed in randomized dilauroylphosphatidylcholine (DLPC)/water/salt mixture and also in randomized palmitoyloleoylphosphatidylcholine (POPC)/water/salt mixture. The resulting membrane-bound full-length structures of P450 1A2 in different membranes were then optimized using coarse-grained and all-atom MD. The resulting models show that, despite of the different membrane thickness, the upper part of the TM helix in both cases directly interacts with a conserved and highly hydrophobic N-terminal proline-rich segment of the catalytic domain. The shallow membrane immersion of the catalytic domain appears to induce a depression in the opposite intact layer of phospholipids, which may help in stabilizing the position of the TM helix directly beneath the catalytic domain. The phospholipid membrane thickness has a direct impact on the TM domain tilt being more inclined in case of the thinner DLPC membrane.
Supported by GACR 18-10251S.