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On the Possibility of the Amphotericin B-Sterol Complex Formation in Cholesterol- and Ergosterol-Containing Lipid Bilayers: A Molecular Dynamics Study
Abstract
Amphotericin B (AmB) is a well-known membrane-active antibiotic that has been used to treat systemicfungal infections for more than 45 years. Therapeutic application of AmB is based on the fact that it is moreactive against ergosterol-containing membranes of fungal cells than against mammalian membranes withcholesterol. In this paper, we examine the hypothesis according to which the selectivity of the AmB's membraneaction originates from its different ability to form the binary complexes with the relevant sterols. To this end,molecular dynamics simulations were performed for systems containing the preformed models of AmB/sterol complexes embedded in lipid bilayers containing either cholesterol or ergosterol. The initial structuresof the studied binary associates were selected on the basis of a systematic scan of all possible mutual positionsand orientations of the two molecules. The results obtained demonstrate that in general the complexes withergosterol are more stable on the 100 ns time scale. Furthermore, on the basis of motional correlation analysis,taking into account the effects of lipid environment, we propose that, within the sterol-enriched liquid-orderedmembrane phases, AmB molecules exhibit a greater tendency to bind ergosterol than cholesterol. The analysisof the interactions suggests that this affinity difference is of enthalpic origin and may arise from the considerabledifference in the energy of the van der Waals interactions between AmB and the two types of sterols. Thus,our current results: (i) support the hypothesis that binary AmB/sterol complexes form within a lipid membraneand (ii) suggest that the higher toxicity may at least partly be attributed to the higher affinity of AmB forergosterol than for cholesterol within a lipid membrane environment.
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- Category:
- Articles
- Type:
- artykuł w czasopiśmie wyróżnionym w JCR
- Published in:
-
JOURNAL OF PHYSICAL CHEMISTRY B
no. 113,
pages 15875 - 15885,
ISSN: 1520-6106 - Language:
- English
- Publication year:
- 2009
- Bibliographic description:
- Neumann A., Czub J., Bagiński M.: On the Possibility of the Amphotericin B-Sterol Complex Formation in Cholesterol- and Ergosterol-Containing Lipid Bilayers: A Molecular Dynamics Study// JOURNAL OF PHYSICAL CHEMISTRY B. -Vol. 113, nr. iss. 48 (2009), s.15875-15885
- DOI:
- Digital Object Identifier (open in new tab) 10.1021/jp905133f
- Verified by:
- Gdańsk University of Technology
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