Temporin L and aurein 2.5 have identical conformations but subtly distinct membrane and antibacterial activities

Giorgia Manzo, Philip M. Ferguson, Charlotte Hind, Melanie Clifford, V. Benjamin Gustilo, Hind Ali, Sukhvinder S. Bansal, Tam T. Bui, Alex F. Drake, R. Andrew Atkinson, J. Mark Sutton, Christian D. Lorenz, David A. Phoenix, A. James Mason*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

Frogs such as Rana temporaria and Litoria aurea secrete numerous closely related antimicrobial peptides (AMPs) as an effective chemical dermal defence. Damage or penetration of the bacterial plasma membrane is considered essential for AMP activity and such properties are commonly ascribed to their ability to form secondary amphipathic, α-helix conformations in membrane mimicking milieu. Nevertheless, despite the high similarity in physical properties and preference for adopting such conformations, the spectrum of activity and potency of AMPs often varies considerably. Hence distinguishing apparently similar AMPs according to their behaviour in, and effects on, model membranes will inform understanding of primary-sequence-specific antimicrobial mechanisms. Here we use a combination of molecular dynamics simulations, circular dichroism and patch-clamp to investigate the basis for differing anti-bacterial activities in representative AMPs from each species; temporin L and aurein 2.5. Despite adopting near identical, α-helix conformations in the steady-state in a variety of membrane models, these two AMPs can be distinguished both in vitro and in silico based on their dynamic interactions with model membranes, notably their differing conformational flexibility at the N-terminus, ability to form higher order aggregates and the characteristics of induced ion conductance. Taken together, these differences provide an explanation of the greater potency and broader antibacterial spectrum of activity of temporin L over aurein 2.5. Consequently, while the secondary amphipathic, α-helix conformation is a key determinant of the ability of a cationic AMP to penetrate and disrupt the bacterial plasma membrane, the exact mechanism, potency and spectrum of activity is determined by precise structural and dynamic contributions from specific residues in each AMP sequence.

Original languageEnglish
Article number10934
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

Bibliographical note

Funding Information:
NMR experiments described in this paper were produced using the facilities of the Centre for Biomolecular Spectroscopy, King’s College London, acquired with a Multi-user Equipment Grant from the Wellcome Trust and an Infrastructure Grant from the British Heart Foundation. CDL acknowledges the stimulating research environment provided by the EPSRC Centre for Doctoral Training in Cross-Disciplinary Approaches to NonEquilibrium Systems (CANES, EP/L015854/1). PMF is supported by a Health Schools Studentship funded by the EPSRC (EP/M50788X/1).

Publisher Copyright:
© 2019, The Author(s).

Fingerprint

Dive into the research topics of 'Temporin L and aurein 2.5 have identical conformations but subtly distinct membrane and antibacterial activities'. Together they form a unique fingerprint.

Cite this