Ion coordination in the amphotericin B channel

Abstract

The antifungal polyene antibiotic amphotericin B forms channels in lipid membranes that are permeable to ions, water, and nonelectrolytes. Anion, cation, and ion pair coordination in the water-filled pore of the "barrel" unit of the channels was studied by molecular dynamics simulations. Unlike the case of the gramicidin A channel, the water molecules do not create a single-file configuration in the pore, and some cross sections of the channel contain three or four water molecules. Both the anion and cation are strongly bound to ligand groups and water molecules located in the channel. The coordination number of the ions is about six. The chloride has two binding sites in the pore. The binding with water is dominant; more than four water molecules are localized in the anion coordination sphere. Three motifs of the ion coordination were monitored. The dominant motif occurs when the anion is bound to one ligand group. The ion is bound to two or three ligand groups in the less favorable configurations. The strong affinity of cations to the channel is determined by the negatively charged ligand oxygens, whose electrostatic field dominates over the field of the hydrogens. The ligand contribution to the coordination number of the sodium ion is noticeably higher than in the case of the anion. As in the case of the anion, there are three motifs of the cation coordination. The favorable one occurs when the cation is bound to two ligand oxygens. In the less favorable cases, the cation is bound to three or four oxygens. In the contact ion pair, the cation and anion are bound to two ligand oxygens and one ligand hydrogen, respectively. There exist intermediate solvent-shared states of the ion pair. The average distances between ions in these states are twice as large as that of the contact ion pair. The stability of the solvent-shared state is defined by the water molecule oriented along the electrostatic field of both ions.

Molecular Properties of Amphotericin B Membrane Channel: A Molecular Dynamics Simulation

“…In addition to experiments, in several recent theoretical studies (8 -14), the focus has been on the isolated molecular properties of AmB or sterols (8 -12). In some of these studies, the channel structure was also considered (13)(14)(15); however, only simple molecular mechanics or electrostatic calculations without proper treatment of the membrane/water environment were used. Ultimately, experimental efforts together with molecular modeling approaches should lead to a more complete understanding of the molecular action of AmB.…”

“…The polar and nonpolar electrostatic potential patterns of the AmB molecule were studied semiquantitatively according to Poisson-Boltzmann methods (18). On the basis of Baginski and Borowski (18) and other studies (4,14,15), it can be assumed that the polar hydroxyl groups of AmB (Fig. 1, top) are placed at the center of the channel and the chain of conjugated CAC bonds interacts with the phospholipid/ sterol environment.…”

“…For example, inwardly pointed hydroxyl groups can interact with the solvent and with the cations inside the channel (15). It has been observed that the charged amino and carboxyl groups of AmB are involved in hydrogen bonding (14,20).…”

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“…4) is the most compact one, and at the same time such structure assures a proper diameter of the pore to be around 0.8 nm. The proposed model of the channel (SLC) is also supported by computational chemistry studies (thermodynamic and electrostatic calculations)68,70,73 which show that through such a channel both potassium and chloride ions can pass freely, as it was observed experimentally 77…”

“…The structure of this channel has never been confirmed by experimental methods. However, many theoretical studies support and use this model 67–74. Moreover, the conformational analysis of AmB membrane channel performed by Silberstein indicates that the stoichiometry proposed originally in the early seventies (i.e., eight AmB molecules per channel) is preferable 72.…”