Determining the effect of the incorporation of unnatural amino acids into antimicrobial peptides on the interactions with zwitterionic and anionic membrane model systems

Amanda L. Russell, Anthony M. Kennedy, Anne M. Spuches, William S. Gibson, Divakaramenon Venugopal, David Klapper, Antoine H. Srouji, Jayendra B. Bhonsle, Rickey P. Hicks

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Circular Dichroism (CD), isothermal calorimetry (ITC) and calcein fluorescence leakage experiments were conducted to provide insight into the mechanisms of binding of a series of antimicrobial peptides containing unnatural amino acids (Ac-XF-Tic-Oic-XK-Tic-Oic-XF-Tic-Oic-XK-Tic-KKKK-CONH 2) to zwitterionic and anionic micelles, SUVs and LUVs; where X (Spacer# 1) is either Gly, β-Ala, Gaba or 6-aminohexanoic acid. It is the intent of this investigation to correlate these interactions with the observed potency and selectivity against several different strains of bacteria. The CD spectra of these compounds in the presence of zwitterionic DPC micelles and anionic SDS micelles are very different indicating that these compounds adopt different conformations on binding to the surface of anionic and zwitterionic membrane models. These compounds also exhibited very different CD spectra in the presence of zwitterionic POPC and anionic mixed 4:1 POPC/POPG SUVs and LUVs, indicating the formation of different conformations on interaction with the two membrane types. This observation is also supported by ITC and calcein leakage data. ITC data suggested these peptides interact primarily with the surface of zwitterionic LUVs and was further supported by fluorescence experiments where the interactions do not appear to be concentration dependent. In the presence of anionic membranes, the interactions appear more complex and the calorimetric and fluorescence data both imply pore formation is dependent on peptide concentration. Furthermore, evidence suggests that as the length of Spacer# 1 increases the mechanism of pore formation also changes. Based on the observed differences in the mechanisms of interactions with zwitterionic and anionic LUVs these AMPs are potential candidates for further drug development.

Original languageEnglish (US)
Pages (from-to)740-758
Number of pages19
JournalChemistry and Physics of Lipids
Volume164
Issue number8
DOIs
StatePublished - Nov 1 2011

Keywords

  • Antimicrobial peptides
  • CD spectroscopy
  • Calcein leakage
  • Fluorescence spectroscopy
  • Isothermal Titration Calorimetry
  • Unnatural amino acids

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Cell Biology

Fingerprint Dive into the research topics of 'Determining the effect of the incorporation of unnatural amino acids into antimicrobial peptides on the interactions with zwitterionic and anionic membrane model systems'. Together they form a unique fingerprint.

  • Cite this

    Russell, A. L., Kennedy, A. M., Spuches, A. M., Gibson, W. S., Venugopal, D., Klapper, D., Srouji, A. H., Bhonsle, J. B., & Hicks, R. P. (2011). Determining the effect of the incorporation of unnatural amino acids into antimicrobial peptides on the interactions with zwitterionic and anionic membrane model systems. Chemistry and Physics of Lipids, 164(8), 740-758. https://doi.org/10.1016/j.chemphyslip.2011.09.003