FU Berlin Digitale Dissertation
Stefan Obst : Exposure of epitopes of bacterial lipopolysaccharides and of their aggregates Exponierung von Epitopen bakterieller Lipopolysaccharide und ihrer Aggregate
|Abstract| |Table of Contents| |More Information|

Abstract Bacterial lipopolysaccharides (LPS, endotoxin) are the causative agent of Gram-negative septicemia frequently leading to death. In the present work, the accessibility of surface structures of LPS-monolayers to LPS-binding molecules was investigated using molecular modelling methods. Based on experimental data and published molecular models, models of the ReLPS of E. coli F515, RcLPS of the J5-mutant of E. coli O111:B4 and the genus-specific LPS of Chlamydia were generated and optimised. LPS monomers were assembled to build monolayers consisting of four to sixteen molecules and subsequently investigated by molecular dynamics simulations (MD) using CHARMm. From the trajectories, the exposed surface of the different components of the LPS molecules was calculated. In addition to calculations carried out in vacuo, other simulations included explicitly modelled water molecules, sodium and calcium ions. Wherever possible, MD simulations were compared to experimental data to ensure the validity of the models: the diffusion coefficient of water molecules as well as the rigidification of LPS-monolayers induced by cations agrees with experimental observations. The profile of the NMR-order parameter SCD and the low percentage of gauche torsions indicate a high state of order of the lipopolysaccharide acyl chains which is observed experimentally as well. The LPS structures investigated expose conformational epitopes hindering the prediction of areas of the LPS molecules which are accessible from the membrane plane from the sequence of core sugar residues. The cross reaction of antibodies directed against the LPS of E. coli J5 and S. minnesota R5 can be explained by the formation of conformational epitopes. The lipid A component of LPS is almost completely covered by LPS core sugar structures and is not accessible in intact LPS monolayers.

Table of Contents Download the whole PhDthesis as a zip-tar file or as zip-File For download in PDF format click the chapter title Titelseite und Inhaltsverzeichnis 1 Einleitung 2 Grundlagen 2.1 Gram-negative Bakterien und ihre Lipopolysaccharide (LPS) 2.2 Molekulardynamik-Simulationen (MD) 3 Material und Methoden 3.1 Computer-Hardware 3.2 Computer-Software 3.3 Lipopolysaccharid-Strukturen 3.4 Bestimmung der Packungsparameter mit MOLECULE 3.5 MD-Simulationen 3.6 Auswertungsverfahren 4 Ergebnisse und Diskussion 4.1 LPS-Moleküle im Vakuum 4.2 Hydratisierte LPS-Aggregate 4.3 Die exponierte Oberfläche 4.4 Konsequenzen für die Erkennung von LPS durch LPS-Bindeproteine und Antikörper 5 Zusammenfassung und Ausblick 6 Anhang 6.1 Literatur 6.2 Glossar 6.3 Danksagung 6.4 Lebenslauf 6.5 Eigene Publikationen

More Information:
Online available:	http://darwin.inf.fu-berlin.de/1998/5/indexe.html
Language of PhDThesis:	german
Keywords:	bacterial lipopolysaccharides; sepsis; molecular dynamic simulation ; monolayer ; epitope; solvent accessible surface
DNB-Sachgruppe:	30 Chemie
Date of disputation:	27-Jul-1998
PhDThesis from:	Fachbereich Biologie, Chemie, Pharmazie, Freie Universität Berlin
First Referee:	Prof. Dr. Hans Bradaczek
Second Referee:	Prof. Dr. Harald Labischinski
Contact (Author):	obst@chemie.fu-berlin.de
Contact (Advisor):	Bradacz@chemie.fu-berlin.de
Date created:	07-Dec-1998
Date available:	30-Aug-1998

 

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