The Effect of Environment on the Recognition and Binding of Vancomycin to Native and Resistant Forms of Lipid II

• Published in: Biophysical journal 2011-12, Vol.101 (11), p.2684-2692
• Main Authors: Jia, ZhiGuang, O'Mara, Megan L., Zuegg, Johannes, Cooper, Matthew A., Mark, Alan E.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; binding capacity; Channels and Transporters; Crystallography, X-Ray; Dimerization; energy; Entropy; glycopeptides; Lipids; membrane fluidity; Membranes; Membranes, Artificial; Models, Molecular; Molecular Conformation; molecular dynamics; Molecular Sequence Data; Molecules; Peptides; Simulation; Structure-Activity Relationship; Uridine Diphosphate N-Acetylmuramic Acid - analogs & derivatives; Uridine Diphosphate N-Acetylmuramic Acid - chemistry; Uridine Diphosphate N-Acetylmuramic Acid - metabolism; vancomycin; Vancomycin - chemistry; Vancomycin - metabolism
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/j.bpj.2011.10.047

Molecular dynamics simulations and free energy calculations have been used to examine in detail the mechanism by which a receptor molecule (the glycopeptide antibiotic vancomycin) recognizes and binds to a target molecule (lipid II) embedded within a membrane environment. The simulations show that the direct interaction of vancomycin with lipid II, as opposed to initial binding to the membrane, leads most readily to the formation of a stable complex. The recognition of lipid II by vancomycin occurred via the N-terminal amine group of vancomycin and the C-terminal carboxyl group of lipid II. Despite lying at the membrane-water interface, the interaction of vancomycin with lipid II was found to be essentially identical to that of soluble tripeptide analogs of lipid II (Ac-d-Ala-d-Ala; root mean-square deviation 0.11 nm). Free energy calculations also suggest that the relative binding affinity of vancomycin for native, resistant, and synthetic forms of membrane-bound lipid II was unaffected by the membrane environment. The effect of the dimerization of vancomycin on the binding of lipid II, the position of lipid II within a biological membrane, and the effect of the isoamylene tail of lipid II on membrane fluidity have also been examined.