title: Mapping multiple potential ATP binding sites on the matrix side of the bovine ADP/ATP carrier by the combined use of MD simulation and docking.
abstract: The mitochondrial adenosine diphosphate/adenosine triphosphate (ADP/ATP) carrier-AAC-was crystallized in complex with its specific inhibitor carboxyatractyloside (CATR). The protein consists of a six-transmembrane helix bundle that defines the nucleotide translocation pathway, which is closed towards the matrix side due to sharp kinks in the odd-numbered helices. In this paper, we describe the interaction between the matrix side of the AAC transporter and the ATP(4-) molecule using carrier structures obtained through classical molecular dynamics simulation (MD) and a protein-ligand docking procedure. Fifteen structures were extracted from a previously published MD trajectory through clustering analysis, and 50 docking runs were carried out for each carrier conformation, for a total of 750 runs ("MD docking"). The results were compared to those from 750 docking runs performed on the X-ray structure ("X docking"). The docking procedure indicated the presence of a single interaction site in the X-ray structure that was conserved in the structures extracted from the MD trajectory. MD docking showed the presence of a second binding site that was not found in the X docking. The interaction strategy between the AAC transporter and the ATP(4-) molecule was analyzed by investigating the composition and 3D arrangement of the interaction pockets, together with the orientations of the substrate inside them. A relationship between sequence repeats and the ATP(4-) binding sites in the AAC carrier structure is proposed.
authors: Department of Medicine, University of Rome Tor Vergata, Rome, Italy.
authors: Daniele
authors: D
authors: Di Marino
authors: Francesco
authors: F
authors: Oteri
authors: Blasco Morozzo
authors: BM
authors: della Rocca
authors: Ilda
authors: I
authors: D'Annessa
authors: Mattia
authors: M
authors: Falconi
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry*; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D016000:Cluster Analysis; D000226:Mitochondrial ADP, ATP Translocases / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013499:Surface Properties; D013816:Thermodynamics
chemical_list: D000255:Adenosine Triphosphate; D000226:Mitochondrial ADP, ATP Translocases