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RESEARCH ARTICLE
Contents Vol 73(3)

Mechanisms of a Small Membrane-Active Antimicrobial Peptide from Hyla punctata

Charles H. Chen https://orcid.org/0000-0001-7695-5215 A C D , Jakob P. Ulmschneider B D and Martin B. Ulmschneider A D
+ Author Affiliations
- Author Affiliations

A Department of Chemistry, King’s College London, London SE1 1DB, UK.

B Institute of Natural Sciences and School of Physics and Astronomy, Shanghai Jiao Tong University, Shanghai 200240, China.

C Current address: Synthetic Biology Group, Research Laboratory of Electronics, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.

D Corresponding authors. Email: chenchar@mit.edu; jakob@sjtu.edu.cn; martin.ulmschneider@kcl.ac.uk

Australian Journal of Chemistry 73(3) 236-245 https://doi.org/10.1071/CH19429
Submitted: 3 September 2019  Accepted: 15 January 2020   Published: 6 February 2020

Abstract

Thousands of antimicrobial peptides have been observed and studied in the past decades; however, their membrane-active mechanisms are ambiguous due to their dynamic structure in the cell membrane. Here, we applied both molecular dynamics (MD) simulations and biophysical experiments to study the small membrane-active antimicrobial peptide Hylaseptin P1 (HSP1), which has significant selectivity towards anionic 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (POPG) and bacterial model membranes. HSP1 does not bind and fold onto human red blood cell model membranes, and it only binds, but does not fold, in zwitterionic 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) membranes. This suggests that the lipid chemistry and membrane rigidity are key to prevent HSP1 binding onto membranes, and the lipid headgroup charge may further promote peptide folding in the membrane. Our experiment-validated MD simulations suggest a carpet-like model mechanism for HSP1 through peptide binding, folding, aggregation, and assembly. HSP1 is shorter than the membrane thickness; therefore, the folded peptides aggregate on the surface, cross the membrane, and the oligomeric structure is supported by several surface-bound peptides in both bilayer leaflets.


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