Catalytic mechanism of l,l-diaminopimelic acid with diaminopimelate epimerase by molecular docking simulations

L. Brunetti, R. Galeazzi, M. Orena, A. Bottoni

Research output: Contribution to journalArticlepeer-review


Peptidoglycan, a key constituent of bacterial cell walls, is currently the target of broad spectrum antibiotics and a new research field involves both design and synthesis of inhibitors of its biosynthesis. Most bacteria require either lysine, or its biosynthetic precursor, diaminopimelate (meso-DAP), as a component of the peptidoglycan layer of the cell wall. In this paper, molecular modelling studies were undertaken in order to shed light on the molecular basis of interaction between (2S,6S)-diaminopimelic acid (l,l-DAP) (1) with its target enzyme DAP-epimerase, since this is a key step in the lysine biosynthetic path leading to (2R,6S)-diaminopimelic acid (meso-DAP) (2). In particular, the docking of the ligand-enzyme complex was studied by means of MD simulations and DFT computations in order to ascertain the optimal structural requirements for the epimerization reaction. Molecular dynamics simulations clearly showed that the configuration of the distal carbon C{single bond}6 of l,l-DAP is critical for complex formation since both amino and carboxylate groups are involved in H{single bond}bonding interactions with the active site residues. Furthermore, the interactions occurring between the functional groups bonded to the C{single bond}2 and some residues of the binding cavity immobilize the ligand in a position appropriate for the epimerization reaction, i.e., exactly in the middle of the two catalytic residues Cys73 and Cys217 as confirmed by DFT quantum mechanical computation of the Michaelis complex. All this mechanistic information could be useful for the rational design of new potential antibiotic drugs effective as inhibitors of peptidoglycan biosynthesis.

Original languageEnglish
Pages (from-to)1082-1090
Number of pages9
JournalJournal of Molecular Graphics and Modelling
Issue number7
Publication statusPublished - Apr 2008


  • DFT
  • Diaminopimelic acid
  • Epimerase
  • Manual docking
  • Molecular dynamics

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Spectroscopy
  • Atomic and Molecular Physics, and Optics


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