Conformational Analysis of Amphotericin B — Cholesterol Channel Complex

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. Contributions of a lactone ring, polar heads, cholesterol and lipid environments to the global energy of the complex formation are discussed. Among the complexes capable of ionic transport, that of axial symmetry eight is preferable. Two types of complexes, differing by the number of intramolecular hydrogen bonds, are shown to be possible.

Molecular modeling of amphotericin B–ergosterol primary complex in water II

“…Similar interactions stabilized to some extent the binary complex; nevertheless the sterol had almost complete conformational freedom there [13]. As presupposed in the hypothetical [5], confirmed in the computational models of other authors [19,22,23] and in our study, the additional stabilizing factors were van der Waals intermolecular forces between AmB and a sterol. Their positioning properties for the sterol molecule arise from its presence in the groove between chromophore systems of AmBs.…”

“…In the vicinity of the polar channel side exposed to water environment the + NH 3 and COO -groups equally distant from one another, as in the primary complexes studied, are to create a multipole of altered positive and negative charges. Such structure was found by Khutorsky [22], Silberstein [23] and Baginski, who moreover observed creation of hydrogen bonds involving these groups [19].…”

“…The absence of these bonds in Khutorsky's model can be interpreted as the cumulated effect of steric hindrance of the neighboring molecules coupled with freezing of the AmB's intramolecular degrees of freedom. Presence of such a set of bonds, intermolecularly connected the polyol systems of antibiotic molecules, was confirmed by Baginski and Silberstein [19,23].…”

“…These claims were partially verified on the basis of a conformational analysis of AmB [24][25][26][27] and the primary complex [12], which demonstrated that due to steric reasons there is low probability of existence of such Silberstein's conformational analysis of the channel demonstrated the presence of the 3βOH-2'OH hydrogen bond [23]. During the simulations of our system orientation of the sterol molecule resulted from relatively intensive H-bonding of 3βOH and polar fragments of the antibiotic molecule (up to 80% of the simulation time).…”

The Design of Molecular Switches for Biosensors

“…[5][6][7][8][9] The presence of the cholesterol molecules in the AmB channel is critical for the channel to be open. 10 The removal of the cholesterol from the channel shuts the channel off. Thus, the switch, in this case, is the modular assembly of the amphotericin pore and the cholesterol gate tethered with the sensing element (antibody, polypeptide, etc.).…”