Simulated dipeptide recognition by vancomycin

Daohui Li, Uma Sreenivasan, Nenad Juranic, Slobodan Macura, Francisco J. Puga, Paul M. Frohnert, Paul H. Axelsen

Research output: Contribution to journalArticle

18 Scopus citations


The antimicrobial activity of vancomycin and related glycopeptide antibiotics is due to stereospecific recognition of polypeptide components in bacterial cell walls. To better understand how these antibiotics recognize polypeptide determinants, we have developed dynamic models of the complexes formed by the vancomycin aglycon and two different dipeptide ligands, Ac-D-ala-D-ala and Ac-D-ala-gly. Molecular dynamics simulations of the two complexes, initially conditioned with distance constraints derived from two-dimensional nuclear magnetic resonance (NMR) studies, are conformationally stable and propagate in a manner consistent with the NMR-derived constraints after the constraints are removed. Free energy calculations accurately predict the relative binding affinity of these two complexes and help validate the simulation models for detailed structural analysis. Although the two ligands adopt similar conformations when bound to the antibiotic, there are clear differences in the configuration of intermolecular hydrogen bonds, the overall shape of the antibiotic, and other structural features of the two complexes. This analysis illustrates how complex structural and dynamic factors interrelate and contribute to differences in binding affinity.

Original languageEnglish (US)
Pages (from-to)73-87
Number of pages15
JournalJournal of Molecular Recognition
Issue number2
StatePublished - Mar 1997


  • 2D NMR
  • Computer-assisted drug design
  • Free energy perturbation
  • Glycopeptide antibiotics
  • Molecular dynamics simulation
  • Molecular recognition
  • Simulated annealing

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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