Molecular basis of the recognition of arachidonic acid by cytochrome P450 2E1 along major access tunnel

Abstract

Cytochrome P450 2E1 is widely known for its ability to oxidize both low molecular weight xenobiotics and endogenous fatty acids (e.g., arachidonic acid (AA)). In this study, we investigated the structural features of the AA-bound CYP2E1 complex utilizing molecular dynamics (MD) and found that the distinct binding modes for both AA and fatty acid analog are conserved. Moreover, multiple random acceleration MD simulations and steered MD simulations uncovered the most possible tunnel for fatty acids. The main attractions are derived from three key residues, His107, Ala108, and His109, whose side chains reorient to keep ligands bound via hydrogen bonds during the initial unbinding process. More importantly, based on the calculated binding free energy results, we hypothesize that the hydrogen bonds between the receptor and the ligand are the most important contributors involved in the binding affinity. Thus, it is inferred that the hydrogen bonds between these three residues and the ligand may help offer insights into the structural basis of the different ligand egress mechanisms for fatty acids and small weight compounds. Our investigation provides detailed atomistic insights into the structural features of human CYP2E1-fatty acid complex structures. Furthermore, the ligand-binding characteristics obtained in the present study are helpful for both experimental and computational studies of CYPs and may allow future researchers to achieve desirable changes in enzymatic activities.

Enzyme Kinetics and Molecular Docking Studies on Cytochrome 2B6, 2C19, 2E1, and 3A4 Activities by Sauchinone

“…Sauchinone exhibited the lowest binding energy of −1.81 kcal/mol at the active site of CYP2E1, consistent with its least inhibition against human CYP2E1 ( K i = 41.70 µM). Active site residues Ile115, Phe207, Phe298, and Ala299 participated in hydrophobic interactions with sauchinone ( Figure 4 G,H) in agreement with previous studies reporting that Ile115, Phe207, Phe298, and Ala299 are responsible for ligand binding to CYP2E1 [ 43 , 44 , 45 ]. These results provided valuable information on structure–activity relationships between sauchinone and CYP2B6, 2C19, 2E1, and 3A4.…”

Asymmetric Binding and Metabolism of Polyunsaturated Fatty Acids (PUFAs) by CYP2J2 Epoxygenase

“…Interestingly, MD simulations of arachidonic acid binding to CYP2E1 also revealed its own unique triad of interacting residues separate from the triad seen in our simulations of CYP2J2 (His 107, Ala 108, and His 109 of CYP2E1). 47 This shows that the residues mediating fatty acid binding to CYPs may not be necessarily conserved, although it may involve a similar triadic theme. Further, since CYP2E1 mainly forms ω-1 and ω-2 hydroxylations, this could explain the differences in the preferred metabolism between CYP2J2 and CYP2E1.…”

Structural analysis of SgvP involved in carbon–sulfur bond formation during griseoviridin biosynthesis

“…8). Moreover, channel 1 and channel 2 may be the solvent and water pathway, respectively [40]. Moreover, channel 1 and channel 2 may be the solvent and water pathway, respectively [40].…”

“…As aromatic residues are located close to the access channels (such as Phe79 and Phe285 in channel 3), they may play a role in recognizing the substrate and help the substrate enter into the active site [39]. Moreover, channel 1 and channel 2 may be the solvent and water pathway, respectively [40].…”