Structural Determinants of Peptide Nanopore Formation

Area of Science:

• Biophysics
• Molecular Biology
• Biochemistry

Background:

• Melittin, a bee venom peptide, broadly permeabilizes membranes.
• Macrolittins, evolved from melittin, exhibit potent membrane selectivity.
• Understanding macrolittin's structural basis for selectivity is key for peptide nanopore applications.

Purpose of the Study:

• To investigate the structural determinants of macrolittin nanopore stability.
• To elucidate the role of hydrogen bonding in macrolittin's membrane selectivity.
• To guide the design of novel peptide nanopore-based applications.

Main Methods:

• Atomistic molecular dynamics simulations.
• Experimental studies on macrolittins and single-site variants.
• Analysis of hydrogen bond networks and lipid conformations.

Main Results:

• Macrolittin nanopores are stabilized by an extensive, cooperative hydrogen bond network.
• This network involves charged/polar side chains, water molecules, and lipid headgroups.
• Variants with altered H-bond networks showed intermediate properties, confirming the network's importance.

Conclusions:

• The membrane-spanning hydrogen bond network is critical for macrolittin nanopore stability and selectivity.
• Lipid molecules in unusual conformations are integral to the nanopore structure.
• Findings will inform the rational design of peptide nanopore applications.