Conformational analysis of amphotericin B--cholesterol channel complex

Area of Science:

• Biophysics
• Molecular Modeling
• Membrane Biophysics

Background:

• Amphotericin B is an antifungal drug that forms pores in cell membranes.
• The exact molecular structure of these pores, particularly the role of cholesterol, remains incompletely understood.
• Previous models often assumed rigid molecular structures, potentially limiting their accuracy.

Purpose of the Study:

• To propose a novel molecular model for the ionic channel formed by amphotericin B and cholesterol.
• To investigate the influence of molecular flexibility on channel structure and stability.
• To identify the preferred complex stoichiometry and structural characteristics for ionic transport.

Main Methods:

• Simulated molecular models of amphotericin B-cholesterol complexes with varying axial symmetry (5 to 11 molecules).
• Analyzed the structural properties, including packing, dispersive forces, and hydrogen bonding.
• Calculated the global energy of complex formation, considering contributions from different molecular components and the lipid environment.

Main Results:

• Flexible amphotericin B and cholesterol molecules form tightly packed, stable channel structures.
• Dispersive forces and intermolecular hydrogen bonds are key to complex consolidation.
• Complexes with axial symmetry eight were found to be energetically favorable and capable of ionic transport.
• Two distinct complex types were identified, differing in intramolecular hydrogen bond numbers.

Conclusions:

• Flexible molecular modeling provides a more accurate representation of amphotericin B-cholesterol ionic channels.
• The axial symmetry eight complex is the most likely configuration for effective ion transport.
• Understanding these interactions is crucial for developing targeted antifungal therapies.