Continuum solvent model calculations of alamethicin-membrane interactions: thermodynamic aspects

Area of Science:

• Biophysics
• Computational Chemistry
• Membrane Biology

Background:

• Alamethicin is a peptide antibiotic forming voltage-gated ion channels.
• Understanding peptide-membrane interactions is crucial for channel function.

Purpose of the Study:

• To calculate the association free energy of alamethicin with lipid bilayers.
• To determine favorable conformations and orientations for alamethicin insertion.
• To investigate the impact of different alamethicin isoforms on membrane association.

Main Methods:

• Continuum solvent models for solvation free energy.
• Statistical thermodynamic model for lipid perturbation and deformation.
• Calculations using NMR and X-ray crystal structures of alamethicin.

Main Results:

• NMR conformations are unfavorable for bilayer partitioning due to uncompensated hydrogen bonds.
• X-ray conformations facilitate membrane association via sufficient hydrogen bonding.
• Transmembrane orientation is the most favorable, with peptide protrusion aligning with experimental data.
• Bilayer deformation of ~2 A is predicted for alamethicin insertion, consistent with experiments.

Conclusions:

• Alamethicin's membrane association is highly dependent on its conformation.
• X-ray conformations are more compatible with lipid bilayer insertion than NMR conformations.
• Calculated orientations and deformations agree well with experimental measurements, supporting the model's validity.