Ion passage pathways and thermodynamics of the amphotericin B membrane channel.
Amphotericin B is a polyene macrolide antibiotic used to treat systemic fungal infections. Amphotericin B's chemotherapeutic action requires the formation of transmembrane channels, which are known to transmit monovalent ions. We have investigated the ion passage pathways through the pore of a realistic model structure of the channel and computed the associated thermodynamic properties. Our calculations combined the free energy computations using the Poisson equation with a continuum solvent model and the molecular simulations in which solvent molecules were present explicitly. It was found that there are no substantial structural barriers to a single sodium or chloride ion passage. Thermodynamic free energy calculations showed that the path along which the ions prefer to move is off center from the channel's central axis. In accordance with experiments, Monte Carlo molecular simulations established that sodium ions can pass through the pore. When it encounters a chloride anion in the channel, the sodium cation prefers to form a solvent-bridged pair configuration with the anion.
Department of Physics, Koç University, Rumelifeneri Yolu, Sariyer, Istanbul, Turkey. haluk.resat@pnl.gov
Haluk
H
Resat
Maciej
M
Baginski
D000666:Amphotericin B / Q000737:chemistry*; D001692:Biological Transport; D002462:Cell Membrane / Q000737:chemistry; D002713:Chlorine / Q000737:chemistry; D003198:Computer Simulation; D006860:Hydrogen Bonding; D007473:Ion Channels / Q000737:chemistry*; D017136:Ion Transport; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009010:Monte Carlo Method; D012680:Sensitivity and Specificity; D012964:Sodium / Q000737:chemistry; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
D007473:Ion Channels; D014867:Water; D002713:Chlorine; D000666:Amphotericin B; D012964:Sodium