title: The effect of environment on the recognition and binding of vancomycin to native and resistant forms of lipid II.
abstract: 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.
authors.affiliation: School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia.
authors.forename: ZhiGuang
authors.initials: Z
authors.lastname: Jia
authors.forename: Megan L
authors.initials: ML
authors.lastname: O'Mara
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuegg
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
authors.forename: Alan E
authors.initials: AE
authors.lastname: Mark
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D019281:Dimerization; D019277:Entropy; D008567:Membranes, Artificial; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D014640:Vancomycin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008567:Membranes, Artificial; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; D014640:Vancomycin