Membrane Association Modes of Natural Anticancer Peptides: Mechanistic Details on Helicity, Orientation, and Surface Coverage

International Journal of Molecular Sciences

Mayra Quemé-Peña¹  Gergely Kohut¹  Imola Cs. Szigyártó¹  Maria Ricci¹  Tamás Beke-Somfai¹  Priyanka Singh¹  Tünde Juhász¹  Lívia Fülöp²  Zita I. Papp² 

[1] Biomolecular Self-Assembly Research Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117 Budapest, Hungary;Department of Medical Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary;

关键词: anticancer peptides;    flow-linear dichroism;    molecular dynamics;    spectroscopy;    peptide conformation;   

DOI  :  10.3390/ijms22168613

来源: DOAJ

【 摘 要 】

Anticancer peptides (ACPs) could potentially offer many advantages over other cancer therapies. ACPs often target cell membranes, where their surface mechanism is coupled to a conformational change into helical structures. However, details on their binding are still unclear, which would be crucial to reach progress in connecting structural aspects to ACP action and to therapeutic developments. Here we investigated natural helical ACPs, Lasioglossin LL-III, Macropin 1, Temporin-La, FK-16, and LL-37, on model liposomes, and also on extracellular vesicles (EVs), with an outer leaflet composition similar to cancer cells. The combined simulations and experiments identified three distinct binding modes to the membranes. Firstly, a highly helical structure, lying mainly on the membrane surface; secondly, a similar, yet only partially helical structure with disordered regions; and thirdly, a helical monomeric form with a non-inserted perpendicular orientation relative to the membrane surface. The latter allows large swings of the helix while the N-terminal is anchored to the headgroup region. These results indicate that subtle differences in sequence and charge can result in altered binding modes. The first two modes could be part of the well-known carpet model mechanism, whereas the newly identified third mode could be an intermediate state, existing prior to membrane insertion.

【 授权许可】

Unknown