title: Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives - A molecular dynamics study.
abstract: Amphotericin B (AmB) is an effective but very toxic antifungal antibiotic. In our laboratory a series of AmB derivatives of improved selectivity of action was synthesized and tested. To understand molecular basis of this improvement, comparative conformational studies of amphotericin B and its two more selective derivatives were carried out in an aqueous solution and in a lipid membrane. These molecular simulation studies revealed that within a membrane environment the conformational behavior of the derivatives differs significantly from the one observed for the parent molecule. Possible reasons for such a difference are analyzed. Furthermore, we hypothesize that the observed conformational transition within the polar head of AmB derivatives may lead to destabilization of antibiotic-induced transmembrane channels. Consequently, the selective toxicity of the derivatives should increase as ergosterol-rich liquid-ordered domains are more rigid and conformationally ordered than their cholesterol-containing counterparts, and as such may better support less stable channel structure.
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Czub
authors.forename: Anna
authors.initials: A
authors.lastname: Neumann
authors.forename: Edward
authors.initials: E
authors.lastname: Borowski
authors.forename: Maciej
authors.initials: M
authors.lastname: Baginski
mesh_terms: D000666:Amphotericin B / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D019277:Entropy; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D013379:Substrate Specificity; D014867:Water / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D008051:Lipid Bilayers; D014867:Water; D000666:Amphotericin B