Experimental and theoretical studies of the structures and interactions of vancomycin antibiotics with cell wall analogues

Surface-induced dissociation (SID) of the singly protonated complex of vancomycin antibiotic with cell wall peptide analogue (N-alpha,N-epsilon-diacetyl-L-LyS-D-Ala-D-Ala) was studied using a 6 T Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (FT-ICR MS) specially configured for SID experiments. The binding energy between the vancomycin and the peptide was obtained from the RRKM modeling of the time- and energy-resolved fragmentation efficiency curves (TFECs) of the precursor ion and its fragments. Molecular dynamics simulations of the vancomycin, pepticle, and vancomycin-peptide complex were carried out to explore the low energy conformations. Density functional theory (DFT) calculations of the geometries, proton affinities, and binding energies were performed for several model systems including vancomycin (V), vancomycin aglycon (VA), N-alpha,N-epsilon-diacetyl-L-Lys-D-Ala-D-Ala, and noncovalent complexes of VA with N-acetyl-D-Ala-D-Ala and V with N-alpha,N-epsilon-diacetyl-L-Lys-D-Ala-D-Ala. Comparison between the experimental and computational results suggests that the most probable structure of the complex observed in our experiments corresponds to the neutral pepticle bound to the vancomycin protonated at the primary amine of the disaccharide group. The experimental binding energy of 30.9 +/- 1.8 kcal/mol is in good agreement with the binding energy of 36.3-42.0 kcal/mol calculated for the model system representing the preferred structure of the complex.