Selective acylation enhances membrane charge sensitivity of the antimicrobial peptide mastoparan-x

Area of Science:

• Biochemistry
• Molecular Biology
• Membrane Biophysics

Background:

• Mastoparan-X (MPX) is a wasp venom peptide known to interact with lipid membranes.
• Understanding peptide-membrane interactions is crucial for drug design, particularly for antimicrobial peptides (AMPs).
• Acylation is a common modification to alter peptide properties, but often affects selectivity negatively.

Purpose of the Study:

• To investigate the effect of N(α)-terminal acylation with propanoic acid (PA) and octanoic acid (OA) on the membrane partitioning of mastoparan-X (MPX).
• To compare the membrane affinity and selectivity of acylated MPX analogs with the native peptide.
• To explore the potential of acylation for fine-tuning peptide selectivity towards negatively charged membranes, such as bacterial membranes.

Main Methods:

• Synthesis of two MPX analogs acylated at the N(α)-terminus with propanoic acid (PA) and octanoic acid (OA).
• Comparative analysis of the partitioning behavior of native MPX and its acylated analogs into neutral and negatively charged lipid membranes.
• Evaluation of membrane affinity and selectivity based on partitioning experiments.

Main Results:

• Acylation significantly altered the membrane partitioning properties of MPX.
• The shorter PA acylation enhanced both affinity and selectivity for negatively charged membranes.
• The longer OA acylation decreased selectivity towards negatively charged membranes.
• This contrasts with previous findings where acylation improved affinity but reduced selectivity.

Conclusions:

• Minor differences in peptide embedding and positioning, induced by PA or OA acylation, critically influence the effective charge and selectivity.
• PA acylation offers a unique method to enhance peptide selectivity for negatively charged membranes.
• This finding may guide the development of AMPs with improved selectivity for bacterial membranes.