title: 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.
authors.affiliation: State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun, People's Republic of China.
authors.forename: Ying-Lu
authors.initials: YL
authors.lastname: Cui
authors.forename: Qing-Chuan
authors.initials: QC
authors.lastname: Zheng
authors.forename: Ji-Long
authors.initials: JL
authors.lastname: Zhang
authors.forename: Hong-Xing
authors.initials: HX
authors.lastname: Zhang
mesh_terms: D016718:Arachidonic Acid / Q000737:chemistry* / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation
chemical_list: D016718:Arachidonic Acid; D019392:Cytochrome P-450 CYP2E1
keywords: MM-GBSA; access tunnels; cytochrome P450; molecular docking; molecular dynamics; steered molecular dynamic