Thermodynamics and kinetics of amphotericin B self-association in aqueous solution characterized in molecular detail

• Published in: Scientific reports Vol. 6; no. 1; p. 19109
• Main Authors: Zielińska, Joanna, Wieczór, Miłosz, Bączek, Tomasz, Gruszecki, Marcin, Czub, Jacek
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.01.2016; Nature Publishing Group
• Subjects: 631/57/2266; 631/92/436; Amphotericin B; Amphotericin B - chemistry; Antifungal agents; Antifungal Agents - chemistry; Aqueous solutions; Biological Transport; Cell Membrane - chemistry; Cell membranes; Cholesterol; Cholesterol - chemistry; Circular Dichroism; Ergosterol; Ergosterol - chemistry; Fungi; Humanities and Social Sciences; Humans; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; Kinetics; Lipid Bilayers - chemistry; Mammals; Membranes; Molecular Dynamics Simulation; Monomers; multidisciplinary; Oligomerization; Science; Self-association; Solutions; Species Specificity; Static Electricity; Thermodynamics; Water - chemistry
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep19109

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.