Mechanism for translocation of fluoroquinolones across lipid membranes

Classical atom-scale molecular dynamics simulations, constrained free energy calculations, and quantum mechanical (QM) calculations are employed to study the diffusive translocation of ciprofloxacin (CPFX) across lipid membranes. CPFX is considered here as a representative of the fluoroquinolone ant...

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Bibliographic Details
Published in:Biochimica et biophysica acta 2012-11, Vol.1818 (11), p.2563-2571
Main Authors: Cramariuc, Oana, Rog, Tomasz, Javanainen, Matti, Monticelli, Luca, Polishchuk, Anna V., Vattulainen, Ilpo
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - metabolism
Biological Transport
Ciprofloxacin
Ciprofloxacin - metabolism
Density functional theory
Fluoroquinolone
Lipid Bilayers
Lipid membrane
Models, Molecular
Molecular dynamics simulations
Quantum Theory
Translocation
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Summary:Classical atom-scale molecular dynamics simulations, constrained free energy calculations, and quantum mechanical (QM) calculations are employed to study the diffusive translocation of ciprofloxacin (CPFX) across lipid membranes. CPFX is considered here as a representative of the fluoroquinolone antibiotics class. Neutral and zwitterionic CPFX coexist at physiological pH, with the latter being predominant. Simulations reveal that only the neutral form permeates the bilayer, and it does so through a novel mechanism that involves dissolution of concerted stacks of zwitterionic ciprofloxacins. Subsequent QM analysis of the observed molecular stacking shows the important role of partial charge neutralization in the stacks, highlighting how the zwitterionic form of the drug is neutralized for translocation. The findings propose a translocation mechanism in which zwitterionic CPFX molecules approach the membrane in stacks, but they diffuse through the membrane as neutral CPFX monomers due to intermolecular transfer of protons favored by partial solvation loss. The mechanism is expected to be of importance in the permeation and translocation of a variety of ampholitic drugs with stacking tendencies. [Display omitted] ► Ciprofloxacin diffuses in water as concerted stacks. ► Stacks of ciprofloxacin dissolve as they enter lipid membranes. ► Translocation of ciprofloxacin through lipid membranes takes place in monomeric form. ► Ciprofloxacin diffuses through a lipid membrane in its neutral form.
ISSN:0005-2736
0006-3002
1879-2642
DOI:10.1016/j.bbamem.2012.05.027