Insights into conformation and membrane interactions of the acyclic and dicarba‑bridged brevinin‑1BYa antimicrobial peptides

PB Timmons, D O'Flynn, JM Conlon, Chandralal Hewage

Research output: Contribution to journalArticle

Abstract

Brevinin-1BYa is a 24-amino acid residue host-defense peptide, first isolated from skin secretions of the foothill yellow-legged frog Rana boylii. The peptide is of interest as it shows broad-spectrum antimicrobial activity and is particularly effective against opportunistic yeast pathogens. Its potential for clinical use, however, is hindered by its latent haemolytic activity. The structures of two analogues, the less haemolytic [C18S,C24S]brevinin1BYa and the more potent trans-dicarba-brevinin-1BYa were investigated in various solution and membrane-mimicking environments by 1HNMR spectroscopy and molecular modelling techniques. Neither peptide possesses a secondary structure in aqueous solution. In both the membrane-mimicking sodium dodecyl sulphate micelles and 33% 2,2,2-trifluoroethanol (TFE-d3)-H2O solvent mixture, the peptides’ structures are characterised by two α-helices connected by a flexible hinge located at the Gly13/Pro14 residues. With the aid of molecular dynamics simulations and paramagnetic probes, it was determined that the peptides’ helical segments lie parallel to the micellar surface, with their hydrophobic residues facing towards the micelle core and the hydrophilic residues pointing outwards, suggesting that both peptides exert their biological activity by a non-pore-forming mechanism. Unlike that of the dicarba analogue, the C-terminus of the acyclic peptide is only weakly associated with the micellar surface and is in direct contact with the surrounding aqueous solvent.
LanguageEnglish
Pages701-710
Number of pages10
JournalEUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS
Volume48
Issue number8
Publication statusAccepted/In press - 13 Aug 2019

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Conformations
Membranes
Peptides
Micelles
Trifluoroethanol
Molecular modeling
Polytetrafluoroethylene
Pathogens
Hinges
Bioactivity
Sodium Dodecyl Sulfate
Yeast
Molecular dynamics
Skin
Spectroscopy
Amino Acids
Computer simulation

Keywords

  • NMR
  • brevinin-1
  • Antimicrobial peptide
  • Molecular modeling

Cite this

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title = "Insights into conformation and membrane interactions of the acyclic and dicarba‑bridged brevinin‑1BYa antimicrobial peptides",
abstract = "Brevinin-1BYa is a 24-amino acid residue host-defense peptide, first isolated from skin secretions of the foothill yellow-legged frog Rana boylii. The peptide is of interest as it shows broad-spectrum antimicrobial activity and is particularly effective against opportunistic yeast pathogens. Its potential for clinical use, however, is hindered by its latent haemolytic activity. The structures of two analogues, the less haemolytic [C18S,C24S]brevinin1BYa and the more potent trans-dicarba-brevinin-1BYa were investigated in various solution and membrane-mimicking environments by 1HNMR spectroscopy and molecular modelling techniques. Neither peptide possesses a secondary structure in aqueous solution. In both the membrane-mimicking sodium dodecyl sulphate micelles and 33{\%} 2,2,2-trifluoroethanol (TFE-d3)-H2O solvent mixture, the peptides’ structures are characterised by two α-helices connected by a flexible hinge located at the Gly13/Pro14 residues. With the aid of molecular dynamics simulations and paramagnetic probes, it was determined that the peptides’ helical segments lie parallel to the micellar surface, with their hydrophobic residues facing towards the micelle core and the hydrophilic residues pointing outwards, suggesting that both peptides exert their biological activity by a non-pore-forming mechanism. Unlike that of the dicarba analogue, the C-terminus of the acyclic peptide is only weakly associated with the micellar surface and is in direct contact with the surrounding aqueous solvent.",
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Insights into conformation and membrane interactions of the acyclic and dicarba‑bridged brevinin‑1BYa antimicrobial peptides. / Timmons, PB; O'Flynn, D; Conlon, JM; Hewage, Chandralal.

In: EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS, Vol. 48, No. 8, 13.08.2019, p. 701-710.

Research output: Contribution to journalArticle

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AU - Timmons, PB

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N2 - Brevinin-1BYa is a 24-amino acid residue host-defense peptide, first isolated from skin secretions of the foothill yellow-legged frog Rana boylii. The peptide is of interest as it shows broad-spectrum antimicrobial activity and is particularly effective against opportunistic yeast pathogens. Its potential for clinical use, however, is hindered by its latent haemolytic activity. The structures of two analogues, the less haemolytic [C18S,C24S]brevinin1BYa and the more potent trans-dicarba-brevinin-1BYa were investigated in various solution and membrane-mimicking environments by 1HNMR spectroscopy and molecular modelling techniques. Neither peptide possesses a secondary structure in aqueous solution. In both the membrane-mimicking sodium dodecyl sulphate micelles and 33% 2,2,2-trifluoroethanol (TFE-d3)-H2O solvent mixture, the peptides’ structures are characterised by two α-helices connected by a flexible hinge located at the Gly13/Pro14 residues. With the aid of molecular dynamics simulations and paramagnetic probes, it was determined that the peptides’ helical segments lie parallel to the micellar surface, with their hydrophobic residues facing towards the micelle core and the hydrophilic residues pointing outwards, suggesting that both peptides exert their biological activity by a non-pore-forming mechanism. Unlike that of the dicarba analogue, the C-terminus of the acyclic peptide is only weakly associated with the micellar surface and is in direct contact with the surrounding aqueous solvent.

AB - Brevinin-1BYa is a 24-amino acid residue host-defense peptide, first isolated from skin secretions of the foothill yellow-legged frog Rana boylii. The peptide is of interest as it shows broad-spectrum antimicrobial activity and is particularly effective against opportunistic yeast pathogens. Its potential for clinical use, however, is hindered by its latent haemolytic activity. The structures of two analogues, the less haemolytic [C18S,C24S]brevinin1BYa and the more potent trans-dicarba-brevinin-1BYa were investigated in various solution and membrane-mimicking environments by 1HNMR spectroscopy and molecular modelling techniques. Neither peptide possesses a secondary structure in aqueous solution. In both the membrane-mimicking sodium dodecyl sulphate micelles and 33% 2,2,2-trifluoroethanol (TFE-d3)-H2O solvent mixture, the peptides’ structures are characterised by two α-helices connected by a flexible hinge located at the Gly13/Pro14 residues. With the aid of molecular dynamics simulations and paramagnetic probes, it was determined that the peptides’ helical segments lie parallel to the micellar surface, with their hydrophobic residues facing towards the micelle core and the hydrophilic residues pointing outwards, suggesting that both peptides exert their biological activity by a non-pore-forming mechanism. Unlike that of the dicarba analogue, the C-terminus of the acyclic peptide is only weakly associated with the micellar surface and is in direct contact with the surrounding aqueous solvent.

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JF - EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS

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