Cooperative Recruitment of Amphotericin B Mediated by a Cyclodextrin Dimer

Abstract

γ-Cyclodextrin (γ-CD) and hydroxypropyl-γ-CD (HP-γ-CD) improve the bioavailability of amphotericin B (AmB) while reducing its toxicity. In a recent study, AmB was found to possess two sites within its prolonged macrolide ring, binding to γ-CD. In the present contribution, cooperative binding of AmB to a γ-CD dimer, a hydroxypropyl-γ-CD (HP-γ-CD) dimer and a hybrid dimer formed by the latter two cyclic oligosaccharides was examined by molecular dynamics simulations and free-energy calculations in an aqueous solution. The potentials of mean force (PMFs) characterizing the dimerization of the CDs on the macrolide ring of AmB were determined for four different spatial arrangements, namely head-to-head (H–H), head-to-tail (H–T), tail-to-head (T–H), and tail-to-tail (T–T). The PMFs allowed the most stable supramolecular organization to be identified along the transition coordinate for every possible orientation of the participating cyclic oligosaccharides. To estimate the absolute binding free energy of each sp...