Membrane Association Modes of Natural Anticancer Peptides: Mechanistic Details on Helicity, Orientation, and Surface Coverage
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 t...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-08-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/16/8613 |
| _version_ | 1797523592789884928 |
|---|---|
| author | Mayra Quemé-Peña Tünde Juhász Gergely Kohut Maria Ricci Priyanka Singh Imola Cs. Szigyártó Zita I. Papp Lívia Fülöp Tamás Beke-Somfai |
| author_facet | Mayra Quemé-Peña Tünde Juhász Gergely Kohut Maria Ricci Priyanka Singh Imola Cs. Szigyártó Zita I. Papp Lívia Fülöp Tamás Beke-Somfai |
| author_sort | Mayra Quemé-Peña |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T08:45:09Z |
| format | Article |
| id | doaj.art-cd011fa815a447bfb36e4259b00a454e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T08:45:09Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-cd011fa815a447bfb36e4259b00a454e2023-11-22T07:57:50ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-012216861310.3390/ijms22168613Membrane Association Modes of Natural Anticancer Peptides: Mechanistic Details on Helicity, Orientation, and Surface CoverageMayra Quemé-Peña0Tünde Juhász1Gergely Kohut2Maria Ricci3Priyanka Singh4Imola Cs. Szigyártó5Zita I. Papp6Lívia Fülöp7Tamás Beke-Somfai8Biomolecular Self-Assembly Research Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117 Budapest, HungaryBiomolecular Self-Assembly Research Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117 Budapest, HungaryBiomolecular Self-Assembly Research Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117 Budapest, HungaryBiomolecular Self-Assembly Research Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117 Budapest, HungaryBiomolecular Self-Assembly Research Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117 Budapest, HungaryBiomolecular Self-Assembly Research Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117 Budapest, HungaryDepartment of Medical Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, HungaryDepartment of Medical Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, HungaryBiomolecular Self-Assembly Research Group, Institute of Materials and Environmental Chemistry, Research Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117 Budapest, HungaryAnticancer 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.https://www.mdpi.com/1422-0067/22/16/8613anticancer peptidesflow-linear dichroismmolecular dynamicsspectroscopypeptide conformation |
| spellingShingle | Mayra Quemé-Peña Tünde Juhász Gergely Kohut Maria Ricci Priyanka Singh Imola Cs. Szigyártó Zita I. Papp Lívia Fülöp Tamás Beke-Somfai Membrane Association Modes of Natural Anticancer Peptides: Mechanistic Details on Helicity, Orientation, and Surface Coverage International Journal of Molecular Sciences anticancer peptides flow-linear dichroism molecular dynamics spectroscopy peptide conformation |
| title | Membrane Association Modes of Natural Anticancer Peptides: Mechanistic Details on Helicity, Orientation, and Surface Coverage |
| title_full | Membrane Association Modes of Natural Anticancer Peptides: Mechanistic Details on Helicity, Orientation, and Surface Coverage |
| title_fullStr | Membrane Association Modes of Natural Anticancer Peptides: Mechanistic Details on Helicity, Orientation, and Surface Coverage |
| title_full_unstemmed | Membrane Association Modes of Natural Anticancer Peptides: Mechanistic Details on Helicity, Orientation, and Surface Coverage |
| title_short | Membrane Association Modes of Natural Anticancer Peptides: Mechanistic Details on Helicity, Orientation, and Surface Coverage |
| title_sort | membrane association modes of natural anticancer peptides mechanistic details on helicity orientation and surface coverage |
| topic | anticancer peptides flow-linear dichroism molecular dynamics spectroscopy peptide conformation |
| url | https://www.mdpi.com/1422-0067/22/16/8613 |
| work_keys_str_mv | AT mayraquemepena membraneassociationmodesofnaturalanticancerpeptidesmechanisticdetailsonhelicityorientationandsurfacecoverage AT tundejuhasz membraneassociationmodesofnaturalanticancerpeptidesmechanisticdetailsonhelicityorientationandsurfacecoverage AT gergelykohut membraneassociationmodesofnaturalanticancerpeptidesmechanisticdetailsonhelicityorientationandsurfacecoverage AT mariaricci membraneassociationmodesofnaturalanticancerpeptidesmechanisticdetailsonhelicityorientationandsurfacecoverage AT priyankasingh membraneassociationmodesofnaturalanticancerpeptidesmechanisticdetailsonhelicityorientationandsurfacecoverage AT imolacsszigyarto membraneassociationmodesofnaturalanticancerpeptidesmechanisticdetailsonhelicityorientationandsurfacecoverage AT zitaipapp membraneassociationmodesofnaturalanticancerpeptidesmechanisticdetailsonhelicityorientationandsurfacecoverage AT liviafulop membraneassociationmodesofnaturalanticancerpeptidesmechanisticdetailsonhelicityorientationandsurfacecoverage AT tamasbekesomfai membraneassociationmodesofnaturalanticancerpeptidesmechanisticdetailsonhelicityorientationandsurfacecoverage |