Mechanism for translocation of fluoroquinolones across lipid membranes

O. Cramariuc, T. Rog, M. Javanainen, L. Monticelli, A. V. Polishchuk, I. Vattulainen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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. (C) 2012 Elsevier B.V. All rights reserved.
OriginalsprogEngelsk
TidsskriftB B A - Biomembranes
Vol/bind1818
Udgave nummer11
Sider (fra-til)2563-2571
Antal sider9
ISSN0005-2736
DOI
StatusUdgivet - 2012

Citer dette

Cramariuc, O., Rog, T., Javanainen, M., Monticelli, L., Polishchuk, A. V., & Vattulainen, I. (2012). Mechanism for translocation of fluoroquinolones across lipid membranes. B B A - Biomembranes, 1818(11), 2563-2571. https://doi.org/10.1016/j.bbamem.2012.05.027
Cramariuc, O. ; Rog, T. ; Javanainen, M. ; Monticelli, L. ; Polishchuk, A. V. ; Vattulainen, I. / Mechanism for translocation of fluoroquinolones across lipid membranes. I: B B A - Biomembranes. 2012 ; Bind 1818, Nr. 11. s. 2563-2571.
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title = "Mechanism for translocation of fluoroquinolones across lipid membranes",
abstract = "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. (C) 2012 Elsevier B.V. All rights reserved.",
author = "O. Cramariuc and T. Rog and M. Javanainen and L. Monticelli and Polishchuk, {A. V.} and I. Vattulainen",
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Cramariuc, O, Rog, T, Javanainen, M, Monticelli, L, Polishchuk, AV & Vattulainen, I 2012, 'Mechanism for translocation of fluoroquinolones across lipid membranes', B B A - Biomembranes, bind 1818, nr. 11, s. 2563-2571. https://doi.org/10.1016/j.bbamem.2012.05.027

Mechanism for translocation of fluoroquinolones across lipid membranes. / Cramariuc, O.; Rog, T.; Javanainen, M.; Monticelli, L.; Polishchuk, A. V.; Vattulainen, I.

I: B B A - Biomembranes, Bind 1818, Nr. 11, 2012, s. 2563-2571.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Mechanism for translocation of fluoroquinolones across lipid membranes

AU - Cramariuc, O.

AU - Rog, T.

AU - Javanainen, M.

AU - Monticelli, L.

AU - Polishchuk, A. V.

AU - Vattulainen, I.

PY - 2012

Y1 - 2012

N2 - 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. (C) 2012 Elsevier B.V. All rights reserved.

AB - 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. (C) 2012 Elsevier B.V. All rights reserved.

U2 - 10.1016/j.bbamem.2012.05.027

DO - 10.1016/j.bbamem.2012.05.027

M3 - Journal article

VL - 1818

SP - 2563

EP - 2571

JO - B B A - Biomembranes

JF - B B A - Biomembranes

SN - 0005-2736

IS - 11

ER -

Cramariuc O, Rog T, Javanainen M, Monticelli L, Polishchuk AV, Vattulainen I. Mechanism for translocation of fluoroquinolones across lipid membranes. B B A - Biomembranes. 2012;1818(11):2563-2571. https://doi.org/10.1016/j.bbamem.2012.05.027