He, Jia; Chipot, Christophe; Shao, Xueguang; Cai, Wensheng
Cooperative Recruitment of Amphotericin B Mediated by a Cyclodextrin Dimer
JOURNAL OF PHYSICAL CHEMISTRY C, 118:24173-24180, OCT 16 2014

gamma-Cyclodextrin (gamma-CD) and hydroxypropyl-gamma-CD (HP-gamma-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 gamma-CD. In the present contribution, cooperative binding of AmB to a gamma-CD dimer, a hydroxypropyl-gamma-CD (HP-gamma-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 (HH), head-to-tail (HT), tail-to-head (TH), and tail-to-tail (TT). 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 spatial arrangement, alchemical transformations were carried out using free-energy perturbation. T-H corresponds to the most stable orientation for the gamma-CD dimer, whereas for the HP-gamma-CD and hybrid dimers, the HT motif is preferred. Our simulations also indicate that, among the three different dimers, the hybrid gamma-CD/HP-gamma-CD possesses the highest binding affinity toward AmB, in line with experiment. Hydrogen-bonding interactions and spatial matching of the host:guest complex play an important role in the cooperative binding of AmB to CD dimers. The difference in the propensity of the three CD dimers to bind AmB can rationalize the experimental observation that the hybrid gamma-CD/HP-gamma-CD dimer is a better carrier to enhance the bioavailability of AmB.

DOI:10.1021/jp507325j

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