New Insights into the Membrane Mechanism of Action of Amphotericin B from Molecular Dynamics Simulations

Abstract

Amphotericin B (AmB) is a well-known polyene antifungal antibiotic that acts by forming channels in cell membranes. It is known that membrane sterols are essential for the AmB biological activity. The selective toxicity of AmB for fungal cells is attributed to the fact that it is more potent against fungal cell membranes containing ergosterol than against the mammalian membranes with cholesterol. There are two non-contradictory models suggesting what this may result from: either from stronger AmB-sterol interactions in case of ergosterol membranes or from a more appropriate environment for the formation of a functional pore provided by more ordered ergosterol-containing membranes.To elucidate the molecular nature of the AmB higher selectivity for ergosterol-containing membranes than for cholesterol-containing ones, we used computational methods and studied (1) the AmB monomer insertion to membranes of different composition (containing or not 30% of ergosterol or cholesterol), (2) the formation of the putative AmB/sterol complexes in a lipid bilayer and (3) the formation of the AmB dimers in a lipid bilayer. To obtain the equilibrium description of these processes the free energy profiles were calculated for each of the studied systems. The significant differences in the affinity of AmB for different membranes have been found. The results indicate that the different behavior patterns of AmB in different membranes is sterol-dependent. The meaning of these differences for the mechanism of action of AmB and, more specifically, for the mechanism of channel formation in different membranes is discussed. The data obtained allowed us also to suggest a possible origin of the increased selectivity towards ergosterol-containing membranes of a novel class of less toxic AmB derivatives.