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Applying internal coordinate mechanics to model the interactions between 8R-lipoxygenase and its substrate.

ABSTRACT: Lipoxygenases (LOX) play pivotal roles in the biosynthesis of leukotrienes and other biologically active potent signalling compounds. Developing inhibitors for LOX is of high interest to researchers. Modelling the interactions between LOX and its substrate arachidonic acid is critical for developing LOX specific inhibitors. Currently, there are no LOX-substrate structures. Recently, the structure of a coral LOX, 8R-LOX, which is 41% sequence identical to the human 5-LOX was solved to 1.85Å resolution. This structure provides a foundation for modelling enzyme-substrate interactions.In this research, we applied a computational method, Internal Coordinate Mechanics (ICM), to model the interactions between 8R-LOX and its substrate arachidonic acid. Docking arachidonic acid to 8R-LOX was performed. The most favoured docked ligand conformations were retained. We compared the results of our simulation with a proposed model and concluded that the binding pocket identified in this study agrees with the proposed model partially.The results showed that the conformation of arachidonic acid docked into the ICM-identified docking site has less energy than that docked into the manually defined docking site for pseudo wild type 8R-LOX. The mutation at I805 resulted in no docking pocket found near Fe atom. The energy of the arachidonic acid conformation docked into the manually defined docking site is higher in mutant 8R-LOX than in wild type 8R-LOX. The arachidonic acid conformations are not productive conformations.We concluded that, for the wild type 8R-LOX, the conformation of arachidonic acid docked into the ICM-identified docking site is more stable than that docked into the manually defined docking site. Mutation affects the structure of the putative active site pocket of 8R-LOX, and leads no docking pockets around the catalytic Fe atom. The docking simulation in a mutant 8R-LOX demonstrated that the structural change due to the mutation impacts the enzyme activity. Further research and analysis is required to obtain the 8R-LOX-substrate model.

SUBMITTER: Bai S

PROVIDER: S-EPMC3026367 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Applying internal coordinate mechanics to model the interactions between 8R-lipoxygenase and its substrate.

Bai Shuju S Du Tianchuan T Khosravi Ebrahim E

BMC bioinformatics 20101007

<h4>Background</h4>Lipoxygenases (LOX) play pivotal roles in the biosynthesis of leukotrienes and other biologically active potent signalling compounds. Developing inhibitors for LOX is of high interest to researchers. Modelling the interactions between LOX and its substrate arachidonic acid is critical for developing LOX specific inhibitors. Currently, there are no LOX-substrate structures. Recently, the structure of a coral LOX, 8R-LOX, which is 41% sequence identical to the human 5-LOX was so ...[more]

PMID: 20946603

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Project description:We present an extension of the all-atom internal-coordinate force field, ICMFF, that allows for simulation of heterogeneous systems including hexopyranose saccharides and glycan chains in addition to proteins. A library of standard glycan geometries containing α- and β-anomers of the most common hexapyranoses, i.e., d-galactose, d-glucose, d-mannose, d-xylose, l-fucose, N-acetylglucosamine, N-acetylgalactosamine, sialic, and glucuronic acids, is created based on the analysis of the saccharide structures reported in the Cambridge Structural Database. The new force field parameters include molecular electrostatic potential-derived partial atomic charges and the torsional parameters derived from quantum mechanical data for a collection of minimal molecular fragments and related molecules. The ϕ/ψ torsional parameters for different types of glycosidic linkages are developed using model compounds containing the key atoms in the full carbohydrates, i.e., glycosidic-linked tetrahydropyran-cyclohexane dimers. Target data for parameter optimization include two-dimensional energy surfaces corresponding to the ϕ/ψ glycosidic dihedral angles in the disaccharide analogues, as determined by quantum mechanical MP2/6-31G** single-point energies on HF/6-31G** optimized structures. To achieve better agreement with the observed geometries of glycosidic linkages, the bond angles at the O-linkage atoms are added to the internal variable set and the corresponding bond bending energy term is parametrized using quantum mechanical data. The resulting force field is validated on glycan chains of 1-12 residues from a set of high-resolution X-ray glycoprotein structures based on heavy atom root-mean-square deviations of the lowest-energy glycan conformations generated by the biased probability Monte Carlo (BPMC) molecular mechanics simulations from the native structures. The appropriate BPMC distributions for monosaccharide-monosaccharide and protein-glycan linkages are derived from the extensive analysis of conformational properties of glycoprotein structures reported in the Protein Data Bank. Use of the BPMC search leads to significant improvements in sampling efficiency for glycan simulations. Moreover, good agreement with the X-ray glycoprotein structures is achieved for all glycan chain lengths. Thus, average/median RMSDs are 0.81/0.68 Å for one-residue glycans and 1.32/1.47 Å for three-residue glycans. RMSD from the native structure for the lowest-energy conformation of the 12-residue glycan chain (PDB ID 3og2) is 1.53 Å. Additionally, results obtained for free short oligosaccharides using the new force field are in line with the available experimental data, i.e., the most populated conformations in solution are predicted to be the lowest energy ones. The newly developed parameters allow for the accurate modeling of linear and branched hexopyranose glycosides in heterogeneous systems.

Dataset Information

Applying internal coordinate mechanics to model the interactions between 8R-lipoxygenase and its substrate.

Publications

Applying internal coordinate mechanics to model the interactions between 8R-lipoxygenase and its substrate.

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