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

J Mol Model. 2012 Jun;18(6):2377-86. doi: 10.1007/s00894-011-1255-5. Epub 2011 Oct 12.

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.

MeSH terms

  • Adenosine Triphosphate / chemistry*
  • Amino Acid Motifs
  • Animals
  • Binding Sites
  • Cattle
  • Cluster Analysis
  • Mitochondrial ADP, ATP Translocases / chemistry*
  • Molecular Dynamics Simulation*
  • Protein Binding
  • Protein Structure, Tertiary
  • Surface Properties
  • Thermodynamics

Substances

  • Adenosine Triphosphate
  • Mitochondrial ADP, ATP Translocases