Table 2.
Positioning of the CYP globular domain with respect to the membrane in the AA MD simulations of CYP 2C9 and CYP 2C19. Values of the mean and standard deviations of angles (as defined in Figure 2) and distances characterizing the positioning of the globular and TM domains were calculated for the last 50 ns of all-atom simulations, with different starting configurations from CG simulations and with different initial velocities assigned. The orientations of the globular domain were assigned to class A, A/B, or B.
| AA MD Simulation | Residues | Angles (°) | Globular Domain-Bilayer Distance (Å) | Class | Time (ns) | ||||
|---|---|---|---|---|---|---|---|---|---|
| TM-Helix | Flexible Linker | α | β | γ | Heme-tilt | ||||
| 2C9:CG:S1 | 3–21 | 22–36 | 91.9 | 111.9 | 17.6 | 30.2 | 45.0 | A | 10,000 2 |
| 2C9:SIM1 | 3–21 | 74.8 ± 4.3 | 119.9 ± 4.5 | 11.9 ± 5.3 | 43.2 ± 4.8 | 45.5 ± 1.5 | A | 216.88 | |
| 2C9:SIM2 1 | 3–21 | 95.9 ± 4.4 | 123.3 ± 4.9 | 13.5 ± 4.1 | 39.8 ± 4.9 | 48.3 ± 2.3 | A | 156.1 | |
| 2C9:CG:S2 | 3–21 | 26–38 | 90.5 | 111.8 | 13.9 | 33.8 | 42.3 | A | 10,000 2 |
| 2C9:SIM3 | 3–21 | 86.6 ± 4.1 | 126.8 ± 3.0 | 5.9 ± 2.7 | 40.1 ± 5.5 | 44.2 ± 0.9 | A/B | 50.6 | |
| 2C19:CG:S1 | 2–23 | 26–38 | 99.6 | 135.3 | 13.0 | 52.4 | 46.7 | B | 10,000 2 |
| 2C19:SIM1 | 2–23 | -- | 106.3 ± 4.2 | 148.6 ± 5.1 | 25.4 ± 7.8 | 60.5 ± 4.5 | 46.2 ± 2.6 | B | 108.4 |
| 2C19:SIM2 1 | 2–23 | -- | 97.0 ± 5.0 | 140.1 ± 4.2 | 25.3 ± 4.6 | 58.1 ± 5.3 | 45.8 ± 1.6 | B | 113.4 |
| 2C19:CG:S2 | 3–21 | 22–36 | 99.5 | 133.3 | 10.2 | 45.9 | 50.3 | B | 10,000 2 |
| 2C19:SIM3 | 3–21 | -- | 94.9 ± 4.8 | 135.8 ± 6.6 | 17.2 ± 4.1 | 55.4 ± 6.5 | 46.0 ± 1.6 | B | 95.2 |
1 Simulated with a ligand in the active site (all other simulations were for the apoproteins). For CYP 2C9, the ligand was flurbiprofen from the crystal structure, and for CYP 2C19, it was the inhibitor from the crystal structure (Protein Data Bank chemical component 0XV). 2 CG simulations were run for an average of 10 µs. The angles were computed for the representative structure that was selected for starting AA MD simulations.