Energy and Entropy Effects in Dissociation of Non-Covalent Complexes: Experimental and Theoretical Investigation of the Structures and Interactions of Glycopeptide Antibiotics-Cell Wall
EMSL Project ID
17499a
Abstract
Energy and Entropy Effects in Dissociation of Non-Covalent Complexes: Experimental and Theoretical Investigation of the Structures and Interactions of Glycopeptide Antibiotics-Cell WallNon-covalent interactions play important roles in biological processes. Dissociation of non-covalent complexes is a focus of extensive research in mass spectrometry. In current study we will use complexes of vancomycin with small peptide as model system to understand the fundamental aspects of biomolecular interactions. Vancomycin is the prototypical glycopeptide antibiotic, and has been widely used in the clinical treatment of methicilin-resistant Stapylococcus (MRSA). Glycopeptide antibiotics target the bacterial cell wall. Specifically, the target of vancomycin, as well as the related antibiotics, is the pentapeptide terminating in L-Lys-D-Ala-D-Ala attached to the MurNAc amino sugar. This type of noncovalent interaction is believed to be the primary antibiotic activity. On the contrary, vancomycin does not show significant binding to L-Ala-L-Ala. However, appearance energy measurement in the gas phase indicate that for positively charged complexes there is no difference in binding energies between vancomycin and these peptides, while significant difference is found in the negative ion mode.
Surface Induced Dissociation (SID) of large molecules by Fourier Transform Ion Cyclotron Resonance mass spectrometry (FT-ICR MS) are experimentally and theoretically studied in our research group. Experimentally we will utilize FT-ICR SID combined with statistical modeling of the experimental data to obtain dissociation energies and activation entropies for dissociation of gas phase complexes of vancomycin. The experimental work will be done as a part of EMSL user proposal 6291. Theoretical electronic structure calculations wil be used to obtain:
(1) the information on the structures and energetics of complex ion dissociation processes, and insight into the non-covalent interactions of the complexes under investigation.
(2) vibrational frequencies of the various complexes that are necessary for accurate modeling of the experimental results.
We plan to perform electronic structure calculations by NWChem on MPP2 using Density-functional Theory (DFT), such as B3LYP, and Hartree-Forck (HF). We expect to finish this project within 1 year (or 75,000 processor hours).
--------------------
Vollmerhaus, P. J.; Breukink, E.; Heck, A. J. R. Chem. Eur. J. 2003, 9, 1556.
Chatterjee, A. N.; Perkins, H. R. Biochem. Biophys. Res. Commun. 1966, 24, 489.
Nieto, M.; Perkins, H. R. Biochem. J. 1971, 123, 789.
Jorgensen, T. J. D.; Delforge, D.; Remacle, J.; Bojensen, G.; Roepstorff, P. Int. J. Mass Spectrom. 1999, 188, 63.
Project Details
Project type
Exploratory Research
Start Date
2006-01-18
End Date
2007-06-26
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Yang Z, ER Vorpagel, and J Laskin. 2008. "Experimental and Theoretical Studies of the Structures and Interactions of Vancomycin Antibiotics with Cell Wall Analogues." Journal of the American Chemical Society 130(39):13013-13022. doi:10.1021/ja802643g
Z. Yang, E. R. Vorpagel, J. Laskin ” Influence of the Charge State on the Structures and Interactions of Vancomycin Antibiotics with Cell Wall Analogue Peptides: Experimental and Theoretical Studies”, Chem. Eur. J., 15, 2081-2090 (2009)