title: Structural dynamics of the mitochondrial ADP/ATP carrier revealed by molecular dynamics simulation studies.
abstract: The mitochondrial adenosine diphosphate/adenosine triphosphate (ADP/ATP) carrier has been recently crystallized in complex with its specific inhibitor carboxyatractyloside (CATR). In the crystal structure, the six-transmembrane helix bundle that defines the nucleotide translocation pathway is closed on the matrix side due to sharp kinks in the odd-numbered helices. The closed conformation is further sealed by the loops protruding into the matrix that interact through an intricate network of charge-pairs. To gain insight into its structural dynamics we performed molecular dynamics (MD) simulation studies of the ADP/ATP carrier with and without its cocrystallized inhibitor. The two trajectories sampled a conformational space around two different configurations characterized by distinct salt-bridge networks with a significant shift from inter- to intrarepeat bonding on the matrix side in the absence of CATR. Analysis of the geometrical parameters defining the transmembrane helices showed that even-numbered helices can undergo a face rotation, whereas odd-numbered helices can undergo a change in the wobble angle with a conserved proline acting as molecular hinge. Our results provide new information on the dynamical properties of the ADP/ATP carrier and for the first time yield a detailed picture of a stable carrier conformation in absence of the inhibitor.
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Falconi
authors.forename: G
authors.initials: G
authors.lastname: Chillemi
authors.forename: D
authors.initials: D
authors.lastname: Di Marino
authors.forename: I
authors.initials: I
authors.lastname: D'Annessa
authors.forename: B
authors.initials: B
authors.lastname: Morozzo della Rocca
authors.forename: L
authors.initials: L
authors.lastname: Palmieri
authors.forename: A
authors.initials: A
authors.lastname: Desideri
mesh_terms: D000818:Animals; D001278:Atractyloside / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D002417:Cattle; D003198:Computer Simulation; D000226:Mitochondrial ADP, ATP Translocases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation
chemical_list: D001278:Atractyloside; D000226:Mitochondrial ADP, ATP Translocases; C003853:carboxyatractyloside