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dc.contributor.advisorBrandsdal, Bjørn Olav
dc.contributor.authorIsaksen, Geir Villy
dc.date.accessioned2010-09-01T10:23:45Z
dc.date.available2010-09-01T10:23:45Z
dc.date.issued2010-06-14
dc.description.abstractIn recent years antimicrobial peptides have gained a lot of attention due to their potential as a new generation of antibiotics combating the growing problem of antibiotic resistance. It is believed that the amphipathic structure of cationic peptides is a key feature for antimicrobial activity, and that this enables them to interact with the bacterial cell membrane. The conformational space of a range of cationic tripeptides have in this project been studied in solvent using density functional theory and molecular dynamics simulations. The results indicate that the cationic tripeptides are able to change between different, but equally stable, conformations that are both amphipathic and non-amphipathic, a property referred to as face flipping. Based on this, face flipping is proposed to be a key feature for the membrane interaction mechanism. The tripeptides mode of interaction was therefore studied with cellular model systems in more detail using MD simulations. The results show that the peptides first interact with the negatively charged head groups of the membrane with their cationic charges and then flip the hydrophobic groups into the membrane bilayer. The results thus provide strong support to the face flipping hypothesis. A problem with antimicrobial peptides is that oral administration is difficult due to the degradation by digestive enzymes. The stability towards chymotryptic degradation has therefore been investigated by probing the S1, S1' and S2' binding pockets with unnatural amino acid side chains. The effect of different side chain substitutions were examined by combining isothermal titration calorimetry, crystallization experiments and extensive molecular modelling. Through these studies it was possible to investigate the preferential binding of several relevant unnatural amino acid side chains to the subsites of chymotrypsin. Important structural and mechanistic features were revealed in a fashion not feasible through the use of native peptide substrates. It was also found that proteolytic stability can be controlled not only by probing the S1 pocket, but also the notably less studied S1' pocket.en
dc.format.extent13690492 bytes
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/10037/2641
dc.identifier.urnURN:NBN:no-uit_munin_2386
dc.language.isoengen
dc.publisherUniversitetet i Tromsøen
dc.publisherUniversity of Tromsøen
dc.rights.accessRightsopenAccess
dc.rights.holderCopyright 2010 The Author(s)
dc.rights.urihttps://creativecommons.org/licenses/by-nc-sa/3.0en_US
dc.rightsAttribution-NonCommercial-ShareAlike 3.0 Unported (CC BY-NC-SA 3.0)en_US
dc.subject.courseIDKJE-3900nor
dc.subjectVDP::Mathematics and natural science: 400::Chemistry: 440::Physical chemistry: 443en
dc.subjectAntimicrobial peptidesen
dc.subjectTripeptidesen
dc.subjectGeometry optimizationen
dc.subjectmolecular dynamicsen
dc.subjectPhase spaceen
dc.subjectFace flippingen
dc.subjectMembrane interactionen
dc.subjectChymotrypsinen
dc.subjectMolecular dockingen
dc.subjectIsothermal titration calorimetryen
dc.subjectMolecular modellingen
dc.subjectCrystallizationen
dc.subjectCrystal structureen
dc.titleFlexible membrane active antimicrobial tripeptides with stability towards chymotryptic degradationen
dc.typeMaster thesisen
dc.typeMastergradsoppgaveen


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