Ion channels formed by amphipathic helical peptides. A molecular modelling study

Area of Science:

• Biophysics
• Molecular Biology
• Computational Chemistry

Background:

• Channel forming peptides (CFPs) are amphipathic molecules that self-assemble into alpha-helical structures within lipid bilayers.
• These peptides form ion channels exhibiting electrophysiological properties similar to protein-based ion channels.
• Understanding CFP structure-function relationships is crucial for biomimetic channel design.

Purpose of the Study:

• To computationally model the structure and ion-binding interactions of two specific CFPs: zervamicin-A1-16 and delta-toxin.
• To investigate the molecular basis of ion permeation and potential gating mechanisms within CFP ion channels.
• To explore the role of specific amino acid residues and backbone carbonyls in K+ ion interactions.

Main Methods:

• Molecular modeling of CFP bundles as parallel trans-bilayer helices.
• Accessible surface area calculations to probe ion-channel interactions.
• Evaluation of van der Waals and electrostatic energy changes during ion translation through the pore.

Main Results:

• Zervamicin-A1-16 channels were modeled as 4-8 helix bundles, with K+ interactions involving backbone carbonyl oxygens.
• Delta-toxin channels were modeled as 6-helix bundles, with residues Q3, D11, and D18 facilitating K+ interactions.
• Rotation of W15 in delta-toxin was identified as a potential mechanism for pore occlusion and channel gating.

Conclusions:

• CFP ion channel structure is characterized by parallel helix bundles surrounding a central pore.
• Specific residues and backbone atoms play critical roles in ion selectivity and binding.
• Conformational changes, such as sidechain rotation, offer plausible models for ion channel gating.