COMPARATIVE-ANALYSIS OF THE DISTRIBUTION OF THE MOLECULAR ELECTROSTATIC POTENTIAL FOR CHOLESTEROL AND ERGOSTEROL

The selective toxicity of the antifungal antibiotic amphotericin B is based on a difference in the affinity of the drug for its cellular tar gets in fungal and mammalian cells which are membrane-located ergoster ol and cholesterol, respectively. The affinity forces comprise van der Waals interactions and hydrogen bonding systems. The comparative anal ysis of the distribution of the molecular electrostatic potential (MEP ) for both sterols was carried out to provide the data for a better un derstanding of the molecular basis for the preferential binding of amp hotericin B to ergosterol compared with cholesterol. The MEP was calcu lated by the semiempirical CNDO/2D method for one selected conformer o f each sterol. The calculations were performed on different planes and presented in the form of maps. The analysis performed revealed the qu alitative differences between cholesterol and ergosterol in the distri bution of the MEP around the side-chain of the sterols. Similarities i n the distribution of the MEP were also found near the hydroxyl group and the ring A of the sterols. The differences found between the elect rostatic patterns of the cholesterol and ergosterol molecules can be r egarded as a source of the higher affinity of amphotericin B for ergos terol than for cholesterol which is observed experimentally. Our resul ts support the hypothesis of a molecular model of a polyene-sterol com plex derived earlier from the experimental data of Herve et al. (Bioch im. Biophys. Acta, 980 (1989) 261).