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The Effect of Sterols on Amphotericin B Self-Aggregation in a Lipid Bilayer as Revealed by Free Energy Simulations
Abstract
Amphotericin B (AmB) is an effective but toxic antifungal drug, known to increase the permeability of the cell membrane, presumably by assembling into transmembrane pores in a sterol-dependent manner. The aggregation of AmB molecules in a phospholipid bilayer is, thus, crucial for the drug’s activity. To provide an insight into the molecular nature of this process, here, we report an atomistic molecular dynamics simulation study of AmB head-to-head dimerization in a phospholipid bilayer, a possible early stage of aggregation. To compare the effect of sterols on the thermodynamics of aggregation and the architecture of the resulting AmB-AmB complexes, free energy profiles for the dimerization in ergosterol- or cholesterol-containing and sterol-free membranes are derived from the simulations. These profiles demonstrate that although AmB dimers are formed in all the systems studied, they are significantly less favorable in the bilayer with ergosterol than in the cholesterol-containing or sterol-free ones. We investigate the structural and energetic determinants of this difference and discuss its consequences for the AmB mechanism of action.
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- Publication version
- Accepted or Published Version
- DOI:
- Digital Object Identifier (open in new tab) 10.1016/j.bpj.2013.02.029
- License
- Copyright (2013 Biophysical Society)
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- Category:
- Articles
- Type:
- artykuł w czasopiśmie wyróżnionym w JCR
- Published in:
-
BIOPHYSICAL JOURNAL
no. 104,
edition 7,
pages 1485 - 1494,
ISSN: 0006-3495 - Language:
- English
- Publication year:
- 2013
- Bibliographic description:
- Neumann A., Bagiński M., Winczewski S., Czub J.: The Effect of Sterols on Amphotericin B Self-Aggregation in a Lipid Bilayer as Revealed by Free Energy Simulations// BIOPHYSICAL JOURNAL. -Vol. 104, iss. 7 (2013), s.1485-1494
- DOI:
- Digital Object Identifier (open in new tab) 10.1016/j.bpj.2013.02.029
- Verified by:
- Gdańsk University of Technology
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