Abstract
Amphotericin B (AmB) is a potent but toxic drug commonly used to treat systemic mycoses. Its efficiency as a therapeutic agent depends on its ability to discriminate between mammalian and fungal cell membranes. The association of AmB monomers in an aqueous environment plays an important role in drug selectivity, as oligomers formed prior to membrane insertion – presumably dimers – are believed to act differently on fungal (ergosterol-rich) and mammalian (cholesterol-rich) membranes. In this work, we investigate the initial steps of AmB self-association by studying the structural, thermodynamic and spectral properties of AmB dimers in aqueous medium using molecular dynamics simulations. Our results show that in water, the hydrophobic aggregation of AmB monomers yields almost equiprobable populations of parallel and antiparallel dimers that rapidly interconvert into each other, and the dipole-dipole interaction between zwitterionic head groups plays a minor role in determining the drug’s tendency for self-aggregation. A simulation of circular dichroism (CD) spectra indicates that in experimental measurements, the signature CD spectrum of AmB aggregates should be attributed to higher-order oligomers rather than dimers. Finally, we suggest that oligomerization can impair the selectivity of AmB molecules for fungal membranes by increasing their hydrophobic drive for non-specific membrane insertion.
Highlights
The spontaneous self-aggregation of AmB in aqueous medium is highly relevant for an alternative mode of action of the drug, put forward by Gray et al.[4]
While these studies reported the coexistence of two dimer geometries, in which the antibiotic molecules are aligned either in a parallel or antiparallel manner, little is known about the equilibrium between them, their structural dynamics and formation kinetics
We quantitatively assessed the thermodynamic stability of various dimer geometries and the associated kinetic parameters, and found that AmB dimers exist in several stable arrangements, with a roughly equiprobable population of parallel and antiparallel arrangements and a sub-microsecond rate of flipping between them
Summary
The spontaneous self-aggregation of AmB in aqueous medium is highly relevant for an alternative mode of action of the drug, put forward by Gray et al.[4]. AmB dimers have been investigated by fluorescence spectroscopy[27,28] and time-resolved single-molecule spectroscopy[29] While these studies reported the coexistence of two dimer geometries, in which the antibiotic molecules are aligned either in a parallel or antiparallel manner, little is known about the equilibrium between them, their structural dynamics and formation kinetics. We quantitatively assessed the thermodynamic stability of various dimer geometries and the associated kinetic parameters, and found that AmB dimers exist in several stable arrangements, with a roughly equiprobable population of parallel and antiparallel arrangements and a sub-microsecond rate of flipping between them. We discuss a possible impact of the hydrophobic solvent-exposed surface area of oligomers on the specificity of drug-membrane interactions, and propose a plausible explanation for the toxic side effects of AmB
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