A computational evaluation of the mechanism of penicillin-binding protein-catalyzed cross-linking of the bacterial cell wall

Qicun Shi, Samy O. Meroueh, Jed F. Fisher, Shahriar Mobashery

Research output: Contribution to journalArticle

19 Scopus citations


Penicillin-binding protein 1b (PBP 1b) of the Gram-positive bacterium Streptococcus pneumoniae catalyzes the cross-linking of adjacent peptidoglycan strands, as a critical event in the biosynthesis of its cell wall. This enzyme is representative of the biosynthetic PBP structures of the β-lactam- recognizing enzyme superfamily and is the target of the β-lactam antibiotics. In the cross-linking reaction, the amide between the -d-Ala-d-Ala dipeptide at the terminus of a peptide stem acts as an acyl donor toward the ε-amino group of a lysine found on an adjacent stem. The mechanism of this transpeptidation was evaluated using explicit-solvent molecular dynamics simulations and ONIOM quantum mechanics/molecular mechanics calculations. Sequential acyl transfer occurs to, and then from, the active site serine. The resulting cross-link is predicted to have a cis-amide configuration. The ensuing and energetically favorable cis- to trans-amide isomerization, within the active site, may represent the key event driving product release to complete enzymatic turnover.(Figure Presented)

Original languageEnglish (US)
Pages (from-to)5274-5283
Number of pages10
JournalJournal of the American Chemical Society
Issue number14
StatePublished - Apr 13 2011


ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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