Membrane interactions and pore formation by the antimicrobial peptide protegrin

Area of Science:

• Biophysics
• Computational Biology
• Antimicrobial Peptides

Background:

• Protegrins are antimicrobial peptides with a characteristic β-hairpin structure.
• Previous studies utilized solid-state NMR and computational methods to investigate protegrin-membrane interactions.
• Existing models suggest specific monomer and dimer associations within membranes.

Purpose of the Study:

• To investigate protegrin monomer binding to membrane surfaces and interiors.
• To analyze the energetics of protegrin dimerization and binding to membrane pores.
• To determine the stability of different protegrin β-barrel structures within pores.

Main Methods:

• Implicit membrane models were employed to study protegrin-membrane interactions.
• Energetic calculations were performed for monomer binding, dimerization, and pore formation.
• Explicit bilayer simulations (100 ns) were conducted to validate structural stability.

Main Results:

• Protegrin monomer burial into the membrane interior is energetically unfavorable.
• Protegrins exhibit weak binding to zwitterionic membrane surfaces but strong binding to toroidal pores.
• Anionic membrane charges enhance protegrin binding via electrostatic interactions.
• Antiparallel NCCN and parallel NCNC octamers demonstrate stability and favorable binding to pores, contrasting with previously proposed NCCN dimers.
• Explicit simulations confirm the superior stability of the parallel NCNC barrel structure.

Conclusions:

• Protegrin's membrane pore formation, particularly in zwitterionic membranes, rationalizes its cytotoxicity.
• The study challenges existing models of protegrin aggregation and membrane interaction.
• Proposed new experiments aim to resolve discrepancies and validate computational findings.