Abstract
Supramolecular assembly and PEGylation (attachment of a polyethylene glycol polymer chain) of peptides can be an effective strategy to develop antimicrobial peptides with increased stability, antimicrobial efficacy and hemocompatibility. However, how the self-assembly properties and PEGylation affect their lipid membrane interaction is still an unanswered question. In this work, we use state-of-the-art small angle X-ray and neutron scattering (SAXS/SANS) together with neutron reflectometry (NR) to study the membrane interaction of a series of multidomain peptides, with and without PEGylation, known to self-assemble into nanofibers. Our approach allows us to study both how the structure of the peptide and the membrane are affected by the peptide–lipid interactions. When comparing self-assembled peptides with monomeric peptides that are not able to undergo assembly due to shorter chain length, we found that the nanofibers interact more strongly with the membrane. They were found to insert into the core of the membrane as well as to absorb as intact fibres on the surface. Based on the presented results, PEGylation of the multidomain peptides leads to a slight net decrease in the membrane interaction, while the distribution of the peptide at the interface is similar to the non-PEGylated peptides. Based on the structural information, we showed that nanofibers were partially disrupted upon interaction with phospholipid membranes. This is in contrast with the considerable physical stability of the peptide in solution, which is desirable for an extended in vivo circulation time.
Highlights
The increase in bacterial resistance to low molecular weight antibiotics has encouraged research into the use of larger peptide or polymer-like molecules as therapeutics, which employ a different antimicrobial mechanism to overcome the existing antibiotic problem
We study the effects of multidomain peptides (MDPs) with and without PEGylation on model lipid membranes using small angle X-ray scattering (SAXS)/SANS and specular neutron re ectometry (NR) at solid–liquid interfaces
We showed that neutron reflectometry (NR) results can be directly compared to results from detailed modelling of small angle X-ray scattering (SAXS) data on monomeric peptide lipid bilayer using supported lipid bilayers (SLBs) or unilamellar vesicles respectively.[31]
Summary
The increase in bacterial resistance to low molecular weight antibiotics has encouraged research into the use of larger peptide or polymer-like molecules as therapeutics, which employ a different antimicrobial mechanism to overcome the existing antibiotic problem. Supramolecular assemblies of antimicrobial peptides (AMPs) have the potential to provide higher efficacy,[1,2,3,4,5] decreased hemolytic response and enhanced stability to serum proteins.[1,2,3,5,6,7,8] Increased activity has been reported by Beter et al upon comparing self-assembled C12VVAGKKKGRW-NH2 and KKKGRW-NH2 nano bers with their. In self-assembled peptides, the surface charge density and charge to surface area ratio differs from that of the single peptide molecules.[15] self-assembly has been related to both the “detergent mechanism”, where the peptides remove lipids from the membrane forming mixed micelles,[16,17] and membrane pore-formation.[18,19] the detailed effect of larger supramolecular assembly and how they structure in the presence of membranes is still an open question
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