Activity determinants of helical antimicrobial peptides: a large-scale computational study

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Antimicrobial peptides (AMPs) are promising novel antibiotics due to their membrane-disrupting mechanisms.
• A central hypothesis posits that AMP activity correlates with binding affinity to anionic (antimicrobial) and zwitterionic (hemolytic) membranes.
• Understanding these interactions is crucial for developing effective AMP-based therapeutics.

Purpose of the Study:

• To test the hypothesis correlating AMP binding affinity with antimicrobial and hemolytic activity.
• To investigate the relationship between AMPs' physical properties and their biological functions.
• To evaluate the applicability of the 'carpet' mechanism versus pore formation for AMPs.

Main Methods:

• Utilized literature-derived and theoretically calculated binding free energies for 53 helical AMPs.
• Employed implicit membrane models to simulate peptide-membrane interactions.
• Analyzed correlations between biological activity and various physical descriptors (e.g., transfer energy, surface area, insertion depth).

Main Results:

• Found weak correlations between binding energy and biological activity, dependent on membrane anionic content.
• Antibacterial activity correlated best with high anionic fraction (>30%), hemolytic activity with low anionic fraction (10%).
• Surface area occupation, insertion depth, and structural fluctuation showed significant correlations with specific activities, and membrane surface coverage at MIC often contradicted the 'carpet' model.

Conclusions:

• The correlation between AMP binding affinity and biological activity is weak and nuanced by membrane composition.
• AMPs active at low surface coverage are more likely pore-formers than carpet-effect agents.
• Transfer energy to toroidal pores is generally favorable, suggesting a role in membrane disruption.