Membrane targeting antimicrobial cyclic peptide nanotubes – an experimental and computational study

Bárbara Claro, Eva González-Freire, Martin Calvelo, Lucinda J. Bessa, Erik Goormaghtigh, Manuel Amorín, Juan R. Granja, Rebeca Garcia-Fandiño, Margarida Bastos

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

The search of new antibiotics, particularly with new mechanisms of action, is nowadays a very important public health issue, due to the worldwide increase of resistant pathogens. Within this effort, much research has been done on antimicrobial peptides, because having the membrane as a target, they represent a new antibiotic paradigm. Among these, cyclic peptides (CPs) made of sequences of D- and L-amino acids have emerged as a new class of potential antimicrobial peptides, due to their expected higher resistance to protease degradation. These CPs are planar structures that can form Self-assembled Cyclic Peptide Nanotubes (SCPNs), in particular in the presence of lipid membranes. Aiming at understanding their mechanism of action, we used biophysical experimental techniques (DSC and ATR-FTIR) together with Coarse-grained molecular dynamics (CG-MD) simulations, to characterize the interaction of these CPs with model membranes of different electrostatic charges’ contents. DSC results revealed that the CPs show a strong interaction with negatively charged membranes, with differences in the strength of interactions depending on peptide and on membrane charge content, at odds with no or mild interactions with zwitterionic membranes. ATR-FTIR suggested that the peptides self-assemble at the membrane surface, adopting mainly a β-structure. The experiments with polarized light showed that in most cases they lie parallel to the membrane surface, but other forms and orientations are also apparent, depending on peptide structure and lipid:peptide ratio. The nanotube formation and orientation, as well as the dependence on membrane charge were also confirmed by the CG-MD simulations. These provide detail on the position and interactions, in agreement with the experimental results. Based on the findings reported here, we could proceed to the design and synthesis of a second-generation CPs, based on CP2 (soluble peptide), with increased activity and reduced toxicity.

Original languageEnglish
Article number111349
JournalColloids and Surfaces B: Biointerfaces
Volume196
DOIs
Publication statusPublished - Dec 2020
Externally publishedYes

Keywords

  • ATR-FTIR
  • Antimicrobial peptides
  • Coarse-Grained
  • D,L-α-cyclic peptides
  • DSC
  • Molecular dynamic simulations
  • Nanotubes
  • Self-Assembly

Fingerprint

Dive into the research topics of 'Membrane targeting antimicrobial cyclic peptide nanotubes – an experimental and computational study'. Together they form a unique fingerprint.

Cite this