title: Computational modelling of the binding of arachidonic acid to the human monooxygenase CYP2J2.
abstract: An experimentally determined structure for human CYP2J2-a member of the cytochrome P450 family with significant and diverse roles across a number of tissues-does not yet exist. Our understanding of how CYP2J2 accommodates its cognate substrates and how it might be inhibited by other ligands thus relies on our ability to computationally predict such interactions using modelling techniques. In this study we present a computational investigation of the binding of arachidonic acid (AA) to CYP2J2 using homology modelling, induced fit docking (IFD) and molecular dynamics (MD) simulations. Our study reveals a catalytically competent binding mode for AA that is distinct from a recently published study that followed a different computational pipeline. Our proposed binding mode for AA is supported by crystal structures of complexes of related enzymes to inhibitors, and evolutionary conservation of a residue whose role appears essential for placing AA in the right site for catalysis. Graphical Abstract Arachidonic acid docked in the active site of CYP2J2 assumes a catalytically competent binding mode stabilised by hydrogen bonds to Arg117.
authors: Department of Pharmaceutical Sciences, Università di Perugia, via del Liceo 1, 06123, Perugia, Italy.|Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, Malet Street, London, WC1E 7HX, UK.
authors: G
authors: G
authors: Proietti
authors: Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, Malet Street, London, WC1E 7HX, UK.|Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London, NW1 0TU, UK.
authors: K K
authors: KK
authors: Abelak
authors: Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London, NW1 0TU, UK.
authors: D
authors: D
authors: Bishop-Bailey
authors: Department of Pharmaceutical Sciences, Università di Perugia, via del Liceo 1, 06123, Perugia, Italy.
authors: A
authors: A
authors: Macchiarulo
authors: Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck, Malet Street, London, WC1E 7HX, UK. i.nobeli@bbk.ac.uk.
authors: I
authors: http://orcid.org/0000-0001-8616-170X
authors: I
authors: Nobeli
mesh_terms: D016718:Arachidonic Acid / Q000737:chemistry* / Q000378:metabolism; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding
chemical_list: C000717350:CYP2J2 protein, human; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2
keywords: Arachidonic acid; CYP2J2; Homology model; Induced fit docking; Molecular dynamics