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Title: Peptide-lipid interactions analyzed via tryptophan derivatives : experimental and computational results
Author: Blaser, Georg
ISNI:       0000 0001 3467 823X
Awarding Body: Durham University
Current Institution: Durham University
Date of Award: 2007
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Tryptophan analogues have been shown to play an important role in the binding and anchoring of peptides in lipid membranes. Mono-substituted tryptophan derivatives were synthesized to study the importance of the relative contribution of electrostatic, quadrupolar and induced dipolar interactions to binding. Binding constants for the adduct formation of amino acid derivatives, lipid molecules and water with themselves and each other were analysed on a molecular level both experimentally, using NMR host-guest titrations and isothermal titration calorimetry (ITC), and computationally via molecular dynamics simulations. Free-energy calculations support the data presented and allowed a quantitative comparison. When free energies of the association of 5-monosubstituted tryptophan analogues (Figure 0.1) with DMPC lipid molecules were plotted against a measure of electron density of the indole ring (the Hammett parameter), an n-shaped pattern was observed. Binding was found to increase for substituted amino acid derivatives with maximal responses for the most electron withdrawing (5-nitro) and the most electron donating (5-methoxy) compounds. This trend was seen both in the titration-data and in the molecular dynamics simulations. The latter allowed the sampling of preferred binding conformations and a determination of the importance of hydrogen bonding and cation-π interactions for and in adduct formation. Additionally, amino acid analogues were incorporated into a model peptide (AcWLWLL) to study the electrostatic effects of the substituent's on the peptide-lipid interactions in the biologically important lipid bilayer environment.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available