Figure 1.
Schematic representation of acetaminophen metabolism by cytochrome P450s.
Figure 2.
Labeling of important atoms of acetaminophen and the heme cluster.
Figure 3.
Docking and MD results for CYP3A4-APAP.
(a) CYP3A4-APAP docking poses feature close proximity of NH-O1 (left) and OH-O1 (right), carbon atoms of the heme and the iron coordinating cysteine residue are colored in cyan, carbon atoms of APAP are colored in purple, iron is shown as a sphere and color in lime (the same color schemes are also used for all other figures). (b) APAP poses identified from MD simulation trajectories, featuring close proximity of NH-O1 (left) and OH-O1 (middle), and close proximity of the C-3 atom to O1 but with no proximity of either NH-O1 or OH-O1 (right). (c) Distribution of RC1 and RC2 in all 15 MD simulations of CYP3A4-APAP with the S1, S2, and S3 states defined. (d) Distribution of RC1 and RC2 for all USP windows.
Figure 4.
Free energy profiles for CYP-APAP binding.
(a) CYP3A4, (b) CYP2E1, (c) CYP2A6, (d) CYP1A2, (e) CYP2C9. Topography energy legend with energy values (kcal/mol) represented by defined color is given in (f). Binding states, S1, S2, S3, S1r and SD are labeled. For CYP2E1, CYP2A6, and CYP1A2, the binding states are clearly defined as energy basins. For CYP3A4 and CYP2C9 where the energy landscape is relatively flat, energy profiles with more color layers are given Figure S4 in Figure S1.
Figure 5.
Active sites snapshots of CYP3A4-APAP.
(a) S1, (b) S2, (c) S3 binding states. The main chain of enzyme residues (other than iron coordinating cysteine) are omitted for clarity unless it forms a H-bond to APAP or it sits very close to APAP (all other figures are shown in a similar manner).
Table 1.
APAP-CYPs regioselectivity determined by experimental data and calculation.
Figure 6.
Top 5 (#1–5) scoring binding poses from CYP2E1-APAP docking results.
Orientation of the views has been kept the same for easy comparison.
Figure 7.
Active site snapshots of CYP2E1-APAP.
(a) S1, (b) S2 states.
Figure 8.
Active site snapshots of CYP2A6-APAP.
(a) S1, (b) S1r, (c) S2, (d) S3 states.
Figure 9.
Cartoon representation of the relative free energy for CYP2A6-APAP metabolism according to the Curtin-Hammett principle.
Figure 10.
Active site snapshots of CYP1A2-APAP.
(a) S1, (b) S2, (c) S3, (d) SD states.
Figure 11.
Active site snapshots of CYP2C9-APAP.
(a) S1, (b) S2, (c) S3, (d) SD states.