title: Prediction of HIV-1 integrase/viral DNA interactions in the catalytic domain by fast molecular docking.
abstract: This study details the separate analyses of binding specificity of HIV-1 integrase (IN) and viral B-DNA forms through ligand-receptor docking studies by means of a fast molecular docking method. The application of solvated electrostatics with the University of Houston Brownian Dynamics Program (UHBD) and configurational sampling by the Daughter of Turnip (DOT) docking program resulted in the computation of energies of more than 113 billion configurations for each ligand-receptor docking study, a procedure considered computationally intractable a few years ago. A specific binding pattern of viral DNA to the IN catalytic domain region has been predicted as a result of these calculations. In a representative docked configuration, we observe the 3'-hydroxyl of the conserved deoxyadenosine to be close to one of the two divalent metal ions that are necessary for catalysis. A superimposition of our energy-minimized docked complex on representative structures from a molecular dynamics (MD) simulation of a crystallographically resolved IN/inhibitor complex revealed an overlap of viral DNA with the inhibitor, indicating that the bound inhibitor might operate by blocking substrate binding. The DOT docking calculation also identified a second, adjacent DNA-binding site, which we believe is the nonspecific host DNA binding site. The binding pattern predicted by DOT complements previous electrostatics, MD simulation, photo-cross-linking, and mutagenesis studies and also provides a further refinement of the IN/viral DNA binding interaction as a basis for new structure-based design efforts.
authors.affiliation: Department of Biology and Biochemistry, Houston Science Center, Room 402D, University of Houston, Houston, Texas 77204-5001, USA.
authors.forename: Adeyemi A
authors.initials: AA
authors.lastname: Adesokan
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Roberts
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
authors.forename: Roberto D
authors.initials: RD
authors.lastname: Lins
authors.forename: James M
authors.initials: JM
authors.lastname: Briggs
mesh_terms: D020134:Catalytic Domain; D004279:DNA, Viral / Q000737:chemistry*; D019427:HIV Integrase / Q000737:chemistry*; D019428:HIV Integrase Inhibitors / Q000737:chemistry; D007211:Indoles / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D013777:Tetrazoles / Q000737:chemistry; D013816:Thermodynamics
chemical_list: C400757:1-(5-chloroindol-3-yl)-3-hydroxy-3-(2H-tetrazol-5-yl)propenone; D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; D007211:Indoles; D008024:Ligands; D013777:Tetrazoles; D019427:HIV Integrase