Abstract
Over the past decade, the rapid increase in the incidence of antibiotic-resistant bacteria has promoted research towards alternative therapeutics such as antimicrobial peptides (AMPs), but their biodegradability limits their application. Encapsulation into nanocarriers based on the self-assembly of surfactant-like lipids is emerging as a promising strategy for the improvement of AMPs' stability and their protection against degradation when in biological media. An in-depth understanding of the interactions between the structure-forming lipids and AMPs is required for the design of nanocarriers. This in silico study, demonstrates the self-assembly of the amphiphilic lipid glycerol monooleate (GMO) with the antimicrobial peptide LL-37 into nanocarriers on the molecular scale. Molecular dynamics (MD) simulations show the formation of direct micelles, with either one or two interacting LL-37, and vesicles in this two-component system in agreement with experimental results from small-angle X-ray scattering studies. The hydrophobic contacts between LL-37 and GMOs in water appear responsible for the formation of these nanoparticles. The results also suggest that the enhanced antimicrobial efficiency of LL-37 in these nanocarriers that was previously observed experimentally can be explained by the availability of its side chains with charged amino acids, an increase of the electrostatic interaction and a decrease of the peptide's conformational entropy upon interacting with GMO. The results of this study contribute to the fundamental understanding of lipid–AMP interactions and may guide the comprehensive design of lipid-based self-assembled nanocarriers for antimicrobial peptides.
Highlights
Antimicrobial peptides (AMPs) have gained increasing attention as a promising alternative to conventional antibiotics due to their unspeci c mode of action and their broad range of activity.[1,2,3,4] their limited stability in biological media due to degradation remains a signi cant challenge for their pharmaceutical application.[5,6,7,8,9]LL-37 is a cathelicidin-derived peptide found in humans that is pivotal for many biological functions
The latter corresponds to a glycerol monooleate (GMO)/LL-37 weight ratio of 1 : 1 that was used in previous experimental studies.[45]
The Molecular dynamics (MD) simulations on GMOs and LL-37 at a weight ratio of 1/1 in water demonstrate their self-assembly into micelles
Summary
LL-37 is a cathelicidin-derived peptide found in humans that is pivotal for many biological functions. It displays broad antimicrobial activity against Gram-positive and negative species,[10,11,12] it can modulate the immune cell response to sites that are infected,[11,13] and it affects the in ammatory reactions of the body.[14,15] LL-37 is composed of 37 residues Of the charged amino acids, 69% are basic, entailing that at a pH of 7, LL-37 carries a net positive charge of 6, an important factor in its antimicrobial activity because of electrostatic attractions to the generally negatively charged microbial cell walls.[16] Another critical aspect of its antimicrobial activity is its secondary structure. Separation of the hydrophobic and hydrophilic groups into two different regions forces LL-37 to either oligomerize with other LL-37 peptides, a process that has recently been proposed as an initial step to destabilize membranes or to interact with the hydrophobic aliphatic chains of lipid membranes.[18,19] Once the concentration of the peptide on the microbe membranes reaches a threshold level, it starts to destabilize it, eventually leading to the pathogen's death.[19,20,21]
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