Membrane insertion of a dinuclear polypyridylruthenium(II) complex revealed by solid-state NMR and molecular dynamics simulation: implications for selective antibacterial activity

Weber, Daniel K., Sani, Marc-Antoine, Downton, Matthew T., Separovic, Frances, Keene, F. Richard, and Collins, J. Grant (2016) Membrane insertion of a dinuclear polypyridylruthenium(II) complex revealed by solid-state NMR and molecular dynamics simulation: implications for selective antibacterial activity. Journal of the American Chemical Society, 138 (46). pp. 15267-15277.

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Abstract

Dinuclear polypyridylruthenium(II) complexes bridged by a flexible methylene linker have received considerable interest as potential antibacterial agents. Their potency and uptake into bacterial cells is directly modulated by the length of the bridging linker, which has implicated membrane interactions as an essential feature of their mechanism of action. In this work, a combination of molecular dynamics (MD) simulations and solid-state NMR was used to present an atomistic model of a polypyridylruthenium(II) complex bound and incorporated into a bacterial membrane model. The results of 31P, 2H, 1H, and 13C NMR studies revealed that the antibacterial [{Ru(phen)2}2(μ-bb12)]4+ complex (Rubb12), where phen = 1,10-phenanthroline and bb12 = bis[4(4'-methyl-2,2'-bipyridyl)]-1,12-dodecane), incorporated into a negatively charged model bacterial membrane, but only associated with the surface of a charge-neutral model of a eukaryotic membrane. Furthermore, an inactive [{Ir(phen)2}2(μ- bb12)]6+ (Irbb12) analogue, which is not taken up by bacterial cells, maintained only a surface-bound association with both bacterial and eukaryotic model membranes according to 31P and 2H NMR. The effects of Rubb12 on 31P chemical shift anisotropy and 2H acyl chain order parameters for negatively charged membranes correlated with a membrane-spanning state of the complex according to MD simulation−in which the metal centers embed in the lipid head group region and the central void, created by the biconic shape of the complex, resulting in increasing disorder of lipid acyl chains and membrane-thinning. A transbilayer mechanism and membrane-spanning may be essential for the cellular uptake and antibacterial activity of this class of compounds.

Item ID: 46297
Item Type: Article (Research - C1)
ISSN: 1520-5126
Keywords: solid-state NMR; molecular dynamics; membrane; antibacterial agent; polypyridyruthenium(II)' membrane
Funders: Australian Postgraduate Award, David Lachlan Hay Memorial Fund, Dowd Foundation
Date Deposited: 10 Nov 2016 02:01
FoR Codes: 03 CHEMICAL SCIENCES > 0302 Inorganic Chemistry > 030201 Bioinorganic Chemistry @ 30%
03 CHEMICAL SCIENCES > 0307 Theoretical and Computational Chemistry > 030799 Theoretical and Computational Chemistry not elsewhere classified @ 30%
06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060106 Cellular Interactions (incl Adhesion, Matrix, Cell Wall) @ 40%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970103 Expanding Knowledge in the Chemical Sciences @ 40%
97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 60%
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