Conformational Analysis of Amphotericin B — Cholesterol Channel Complex
Institute of Theoretical and Experimental Biophysics of Russian Academy of Science, Puschino, 142292 Russia
Received: 25 April 1997/Revised: 20 November 1997
Abstract. A molecular model of ionic channel formed by
flexible molecules of amphotericin B and cholesterol is
proposed. Complexes with axial symmetry from 5 to 11
were simulated. In contrast to the model of the channel
formed from rigid molecules, flexible molecules form a
tightly packed structure consolidated by both dispersive
forces and intermolecular hydrogen bonds. Contribu-
tions of a lactone ring, polar heads, cholesterol and lipid
environments to the global energy of the complex for-
mation are discussed. Among the complexes capable of
ionic transport, that of axial symmetry eight is prefer-
able. Two types of complexes, differing by the number
of intramolecular hydrogen bonds, are shown to be pos-
Key words: Amphotericin B — Cholesterol — Ionic
channel structure — Conformational analysis
The polyene antibiotic amphotericin B is known to in-
duce ionic transport in biological membranes [3, 20].
It was also shown to form ionic channels in black lipid
membranes [7, 8]. The presence of sterol molecules in
the membrane is necessary for channel formation. The
channels are permeable to univalent ions and small or-
ganic compounds . Qualitative models of the channel,
based on its transport properties and structural peculiari-
ties of the amphotericin B molecule, were proposed by
Andreoli , De Kruijff and Demel  and Finkelstein
and Holz . However, these models are too simplistic
to allow simulation of the channel transport properties at
the molecular level.
The chemical structure of the amphotericin B mol-
ecule was determined by Borowski et al. . The spatial
structure of its iodinated derivative was solved by Ganis
et al. . Conformational analysis of a free amphoteri-
cin molecule or its complexes is hampered due to the
presence of a macrolide lactone ring in the molecule.
This problems was resolved by Rinnert and Maigret .
The stable structure found in a vacuum approximation
was shown to be similar to that in the crystalline state.
NMR stereochemical data obtained by Sowinski et al.
 have shown the identity of the antibiotic conforma-
tion in solution and in the crystal. Based on these find-
ings, some models of the ionic channel made of rigid
molecules of the antibiotic and sterol were proposed by
Khutorsky et al. [16, 18, 19]. Attempts to conduct a
simulation of electric properties of the channel based on
the models made from the rigid molecules have been
published [4, 17].
There is no reason to expect large energetic hin-
drances in a conformational mobility of the amphotericin
B lactone ring. The rigid frame of the ring does not
allow tight packing of the channel structure; while one
may suppose that only a tightly packed structure of the
ionic channel ensures stability of its basic properties such
as ionic selectivity and permeability.
The problem of amphotericin B molecule flexibility
was resolved by Mazerski and Borowski  using a
molecular dynamics method. In contrast to Rinnert and
Maigret , they demonstrated that a variety of confor-
mational states of the amphotericin B molecule with sig-
nificantly different values of dihedral angles are possible.
A molecular conformation is largely determined by
its environment. This general statement is supported by
the results of amphotericin B molecule simulations by
Mazerski and Borowski . The significant differences
in the conformations of the molecule in a vacuum and in
an aqueous environment were shown.
* Present address: Laboratory of Gene Therapy, School of Medicine,
University of Southern California, 1441 Eastlake Ave., Los Angeles,
CA 90033, USA
Correspondence to: A. Silberstein
J. Membrane Biol. 162, 117–126 (1998)
The Journal of
© Springer-Verlag New York Inc. 1998