Structure of vancomycin and a vancomycin/D-Ala-D-Ala complex in solution.

Restrained molecular dynamics simulations were used to study the interactions between the glycopeptide antibiotic vancomycin and the dipeptide Ac-D-Ala-D-Ala. Restraints were obtained from a combination of homonuclear and heteronuclear two-dimensional NMR experiments (NOESY, ROESY, 1H-15N inverse correlation). The comparison between the structures obtained for vancomycin alone and for the complex suggests a new hypothesis on the binding mode of this system. The numerical simulations were not straightforward because vancomycin is made of building blocks for which standard force-fields are not available. The representation of unusual chemical environments is also mandatory. We believe that our extension of the force-field parameters to our system could be of more general interest. Furthermore, we consider vancomycin and its complex a good example for exploring the more general problem of molecular recognition, a challenge that has been widely approached in the past few years but for which no unique and general methodology has, so far, been recognized.