Evolution-driven terminal capping design in antimicrobial peptides revealed by combined experimental and MD...

Area of Science:

• Biochemistry
• Molecular Biology
• Biophysics

Background:

• Natural antimicrobial peptides commonly feature terminal modifications like N-terminal free amino groups and C-terminal amidation.
• These structural motifs are hypothesized to enhance antimicrobial activity, but the underlying molecular mechanisms require further elucidation.

Purpose of the Study:

• To systematically investigate the impact of terminal capping on the antimicrobial peptide Mastoparan C (MPC).
• To understand the molecular rationale behind the evolutionarily favored terminal modifications in antimicrobial peptides.

Main Methods:

• Preparation of three Mastoparan C analogs with varied terminal capping groups.
• Structural and biological evaluations of the analogs.
• Molecular dynamics (MD) simulations to analyze peptide-membrane interactions.

Main Results:

• The combination of a free amino group at the N-terminus and C-terminal amidation resulted in the highest antibacterial potency and selectivity for Mastoparan C analogs.
• Terminal modifications were shown to optimize the ability of peptides to disrupt microbial membranes while maintaining selectivity.

Conclusions:

• The common terminal capping design in antimicrobial peptides is an evolutionary adaptation to enhance functional performance.
• Findings provide insights into the design principles of antimicrobial peptides and guide the development of novel therapeutic agents.