Abstract
We addressed the onset of synergistic activity of the two well-studied antimicrobial peptides magainin 2 (MG2a) and PGLa using lipid-only mimics of Gram-negative cytoplasmic membranes. Specifically, we coupled a joint analysis of small-angle x-ray and neutron scattering experiments on fully hydrated lipid vesicles in the presence of MG2a and L18W-PGLa to all-atom and coarse-grained molecular dynamics simulations. In agreement with previous studies, both peptides, as well as their equimolar mixture, were found to remain upon adsorption in a surface-aligned topology and to induce significant membrane perturbation, as evidenced by membrane thinning and hydrocarbon order parameter changes in the vicinity of the inserted peptide. These effects were particularly pronounced for the so-called synergistic mixture of 1:1 (mol/mol) L18W-PGLa/MG2a and cannot be accounted for by a linear combination of the membrane perturbations of two peptides individually. Our data are consistent with the formation of parallel heterodimers at concentrations below a synergistic increase of dye leakage from vesicles. Our simulations further show that the heterodimers interact via salt bridges and hydrophobic forces, which apparently makes them more stable than putatively formed antiparallel L18W-PGLa and MG2a homodimers. Moreover, dimerization of L18W-PGLa and MG2a leads to a relocation of the peptides within the lipid headgroup region as compared to the individual peptides. The early onset of dimerization of L18W-PGLa and MG2a at low peptide concentrations consequently appears to be key to their synergistic dye-releasing activity from lipid vesicles at high concentrations.
Highlights
The steady increase of antibiotic resistance of pathogenic bacteria, combined with the decline of approved antimicrobial agents, is considered to be a severe threat to global health
We demonstrate that specific interactions of the antimicrobial peptides magainin 2-amide (MG2a) and PGLa with each other in POPE/POPG bilayers lead to the formation of surface-aligned parallel dimers, which already provide, at low peptide concentrations, the nucleus for the peptides’ well-known synergistic activity
Based on experimental evidence for surface-aligned topologies of MG2a and L18W-PGLa in POPE/POPG (3:1 mol/mol) [13], as well as our own molecular dynamics (MD) simulations results, we modeled the contribution of the peptides by a single Gaussian volume probability function centered at zp in the headgroup regime
Summary
The steady increase of antibiotic resistance of pathogenic bacteria, combined with the decline of approved antimicrobial agents, is considered to be a severe threat to global health. In view of these developments, considerable research efforts have been devoted to understanding the mode of action of antimicrobial peptides (AMPs), considered as an alternative for the development of novel antibiotics. 1858 Biophysical Journal 117, 1858–1869, November 19, 2019 within minutes, which makes it more difficult for bacteria to develop resistance mechanisms (for review, see, e.g., [1,2]). Applying diverse biophysical techniques on lipidonly membrane mimics, several interaction models have been conceived for AMPs [1,3,4]. Pore formation is arguably the most widely discussed membrane disruptive mechanism
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