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Ion passage pathways and thermodynamics of the amphotericin B membrane channel
1Department of Physics, Koç University, Rumelifeneri Yolu, Sariyer, Istanbul, Turkey. haluk.resat@pnl.gov
Abstract:
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.
Insights
Amphotericin B forms channels for ion passage during fungal infection treatment. Studies reveal sodium and chloride ions move through the pore, with sodium ions forming pairs with chloride anions within the channel.
Area of Science:
- Biophysics
- Computational Chemistry
- Pharmacology
Background:
- Amphotericin B is a polyene macrolide antibiotic crucial for treating systemic fungal infections.
- Its therapeutic effect relies on forming transmembrane channels that facilitate monovalent ion transport.
Purpose of the Study:
- To investigate ion passage pathways within a realistic model of the Amphotericin B channel.
- To compute the thermodynamic properties associated with ion permeation through the channel pore.
Main Methods:
- Utilized free energy computations employing the Poisson equation with a continuum solvent model.
- Performed molecular simulations with explicit solvent molecules to model ion transport.
Main Results:
- Identified no significant structural barriers for individual sodium (Na+) or chloride (Cl-) ion passage.
- Thermodynamic free energy calculations indicated an off-center preferred pathway for ion movement.
- Monte Carlo simulations confirmed sodium ion permeation and revealed a preference for forming solvent-bridged pairs with chloride anions within the channel.
Conclusions:
- The study elucidates the mechanism of ion permeation through Amphotericin B channels.
- Findings provide insights into the molecular interactions governing ion transport, particularly the sodium-chloride interaction, relevant to the drug's function.