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Effect of lipid headgroup composition on the interaction between melittin and lipid bilayers
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0001-9070-6944
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
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2007 (English)In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 311, no 1, 59-69 p.Article in journal (Refereed) Published
Abstract [en]

The effect of the lipid polar headgroup on melittin-phospholipid interaction was investigated by cryo-TEM, fluorescence spectroscopy, ellipsometry, CD, electrophoresis and photon correlation spectroscopy. In particular, focus was placed on the effect of the lipid polar headgroup on peptide adsorption to, and penetration into, the lipid bilayer, as well as on resulting colloidal stability effects for large unilamellar liposomes. The effect of phospholipid headgroup properties on melittin-bilayer interaction was addressed by comparing liposomes contg. phosphatidylcholine, -acid, and -inositol at varying ionic strength. Increasing the bilayer neg. charge leads to an increased liposome tolerance toward melittin which is due to an electrostatic arrest of melittin at the membrane interface. Balancing the electrostatic attraction between the melittin pos. charges and the phospholipid neg. charges through a hydration repulsion, caused by inositol, reduced this surface arrest and increased liposome susceptibility to the disruptive actions of melittin. Furthermore, melittin was demonstrated to induce liposome structural destabilization on a colloidal scale which coincided with leakage induction for both anionic and zwitterionic systems. The latter findings thus clearly show that coalescence, aggregation, and fragmentation contribute to melittin-induced liposome leakage, and that detailed mol. analyses of melittin pore formation are incomplete without considering also these colloidal aspects.

Place, publisher, year, edition, pages
2007. Vol. 311, no 1, 59-69 p.
Keyword [en]
Adsorption, Bilayer, Circular dichroism, Ellipsometry, Fluorescence, Liposome, Melittin
National Category
Chemical Sciences Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-10915DOI: 10.1016/j.jcis.2007.02.070ISI: 000246925700008PubMedID: 17383670OAI: oai:DiVA.org:uu-10915DiVA: diva2:38683
Available from: 2007-10-01 Created: 2007-10-01 Last updated: 2017-12-11
In thesis
1. Physico-Chemical Investigations of, and Characterization of Model Membranes for, Lipid-Peptide Interactions
Open this publication in new window or tab >>Physico-Chemical Investigations of, and Characterization of Model Membranes for, Lipid-Peptide Interactions
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The main focus of this thesis is on the effects caused by α-helical peptides on liposome structure, the impact of cholesterol on the peptide-membrane interactions, and the effect of aggregate curvature on the peptide affinity. Results of the studies show that the membrane destabilizing effect of the cationic α-helical peptide melittin is modulated by cholesterol. Melittin induces leakage from pure phospholipid liposomes in a manner that is compatible with the presence of small pores. In the case of cholesterol-supplemented liposomes leakage coincides, however, with major structural transformations and rupture of the liposomes. Cholesterol decreases the affinity of melittin for phospholipid bilayers, but once the peptide has adsorbed to the membrane the presence of cholesterol does not offer any resistance against melittin-induced membrane destabilization. Our investigations indicate that cholesterol affects the alamethicin-lipid bilayer interactions in a similar way.

PEG-stabilized bilayer disks are formed upon addition of polyethylene glycol (PEG)-lipids to lipid mixtures with high bending rigidity. The partial segregation of components within the bilayer disk, suggested by theoretical calculations and experimental observations, was verified by small angle neutron scattering. By means of a novel competitive binding assay it was shown that the three α-helical peptides melittin, alamethicin, and magainin have high affinity for the curved rim of PEG-stabilized bilayer disks. The bilayer disks have structural, and other properties, that make them interesting for the formulation of peptides and membrane-associated proteins. For stability reasons dry formulations are often preferred. The PEG-stabilized bilayer disks were shown to retain their structure in rehydrated samples that had been freeze- or spray-dried in the presence of lactose.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2009. 63 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 610
National Category
Physical Chemistry
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-89432 (URN)978-91-554-7436-2 (ISBN)
Public defence
2009-03-27, B22, BMC, Husargatan 3, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2009-03-06 Created: 2009-02-13 Last updated: 2009-03-26
2. Antimicrobial Peptide Interactions with Phospholipid Membranes: Effects of Peptide and Lipid Composition on Membrane Adsorption and Disruption
Open this publication in new window or tab >>Antimicrobial Peptide Interactions with Phospholipid Membranes: Effects of Peptide and Lipid Composition on Membrane Adsorption and Disruption
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The interactions between antimicrobial peptides and phospholipid membranes were investigated, in terms of lipid headgroup variations and the role of cholesterol, as well as peptide composition and structure. Also strategies for increasing proteolytic stability were evaluated. The interactions were studied on model membranes in the form of liposomes and supported bilayers, through a combination of ellipsometry, fluorescence spectroscopy, circular dichroism, dynamic light scattering, electrophoresis, electron cryomicroscopy, and bacterial/cell culture experiments.

The findings showed that membrane tolerance against the lytic activity of melittin, was increased on anionic membranes by electrostatic arrest in the headgroup region, and was reduced by hydration repulsion. The presence of cholesterol caused a reduction in melittin adsorption, while at the same time reducing membrane tolerance per adsorbed peptide. Differences in membrane leakage mechanisms were also attributed to cholesterol, where large scale structural effects contributed to the leakage, while other membranes followed the pore formation model.

Substituting specific amino acids for tryptophan on an LL-37 derivative, was shown to increase stability against bacterial proteases, while at the same time significantly increasing antibacterial properties. These substitutions, as well as terminal modifications, increased adsorption and membrane lytic properties in a way that was less dependent on electrostatics. Furthermore, by comparing short cationic peptides with oligotryptophan end-tagged versions, the lytic mechanism of end-tagged peptides, and the different contributions of arginine and lysine to membrane adsorption and disruption were demonstrated.

This thesis is a contribution to the development of antimicrobial peptides as therapeutic alternatives to conventional antibiotics.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 97
Keyword
antimicrobial, peptide, adsorption, liposome, membrane, melittin, cholesterol, tryptophan, phospholipid, bilayer
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-100966 (URN)978-91-554-7520-8 (ISBN)
Public defence
2009-05-20, B42, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2009-04-29 Created: 2009-04-15 Last updated: 2009-05-12Bibliographically approved

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Wessman, PerRingstad, LovisaEdwards, KatarinaMalmsten, Martin

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