Folding and aggregation of amyloid peptides [Elektronische Ressource] / Madeleine Kittner. Betreuer: Robert Seckler

Madeleine Kittner

Sujets

• Biologie

Informations

• Publié par: universitat_potsdam
• Publié le: 01 janvier 2011
• Nombre de lectures: 28
• Langue: English
• Poids de l'ouvrage: 5 Mo

Extrait

¨Max-Planck-Institut fur Kolloid- und
¨Grenzflachenforschung
Abteilung: Theorie und Bio-Systeme
Folding and Aggregation of Amyloid Peptides.
von
Madeleine Kittner
Dissertation
zur Erlangung des akademischen Grades
Doktor der Naturwissenschaften (Dr. rer. nat.)
in der Wissenschaftsdisziplin Physikalische Biochemie
eingereicht an der
Mathematisch-Naturwissenschaftlichen Fakulta¨t
der Universita¨t Potsdam
Potsdam, im April 2011This work is licensed under a Creative Commons License:
Attribution - Noncommercial - Share Alike 3.0 Germany
To view a copy of this license visit
http://creativecommons.org/licenses/by-nc-sa/3.0/de/









































Published online at the
Institutional Repository of the University of Potsdam:
URL http://opus.kobv.de/ubp/volltexte/2011/5357/
URN urn:nbn:de:kobv:517-opus-53570
http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-53570 Contents
1 Introduction 7
1.1 Folding and aggregation of polypeptides . . . . . . . . . . . . . . . . . . . 8
1.1.1 Structure of amyloid fibrils . . . . . . . . . . . . . . . . . . . . . . 12
1.1.2 Models for fibril formation . . . . . . . . . . . . . . . . . . . . . . . 13
1.1.3 Toxic oligomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
1.2 Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
1.2.1 Molecular basis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
1.2.2 Neurotoxicity of A . . . . . . . . . . . . . . . . . . . . . . . . . . 20
1.2.3 Drug design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
1.3 Objectives and questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2 Molecular Dynamics Simulation and Analysis Methods 23
2.1 Principle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.2 Force fields . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.2.1 Force fields used for peptides . . . . . . . . . . . . . . . . . . . . . 27
2.2.2 Force fields used for water . . . . . . . . . . . . . . . . . . . . . . . 27
2.3 Computing trajectories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.3.1 Integration algorithm . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.3.2 Periodic boundary conditions . . . . . . . . . . . . . . . . . . . . . 28
2.3.3 Temperature and pressure coupling . . . . . . . . . . . . . . . . . . 30
2.3.4 Position restraints . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
2.3.5 Improving efficiency . . . . . . . . . . . . . . . . . . . . . . . . . . 32
2.4 Replica exchange method . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
2.5 Energy minimization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
2.6 Analysis methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
2.6.1 Radius of gyration . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
2.6.2 Root mean square deviation . . . . . . . . . . . . . . . . . . . . . . 35
2.6.3 Secondary structure of proteins (DSSP) . . . . . . . . . . . . . . . 36
2.6.4 Cluster analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
2.6.5 Solvent accessible surface area and solvation free energy . . . . . . 37
3CONTENTS
2.6.6 Hydrogen bond and side chain contact maps . . . . . . . . . . . . 37
2.6.7 Principal component analysis . . . . . . . . . . . . . . . . . . . . . 37
2.6.8 Free energy landscape . . . . . . . . . . . . . . . . . . . . . . . . . 38
2.6.9 Free energy, potential energy and entropy of transitions . . . . . . 39
2.6.10 Error estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3 Simulation Results for A(25-35) 41
3.1 Previous experimental and theoretical observations . . . . . . . . . . . . . 41
3.2 System setup and equilibration . . . . . . . . . . . . . . . . . . . . . . . . 42
3.3 Conformation of monomers . . . . . . . . . . . . . . . . . . . . . . . . . . 45
3.4 Conformational diversity of dimers . . . . . . . . . . . . . . . . . . . . . . 45
3.4.1 Analysis of conformational clusters . . . . . . . . . . . . . . . . . . 47
3.4.2 Transition from disordered to fibril-like dimers . . . . . . . . . . . 53
3.4.3 Interactions stabilizing compact and extended dimer conformations 54
3.4.4 Critical dimer concentration . . . . . . . . . . . . . . . . . . . . . . 57
3.5 Conformational ensemble of trimers . . . . . . . . . . . . . . . . . . . . . 58
3.5.1 Analysis of conformational clusters . . . . . . . . . . . . . . . . . . 58
3.5.2 Free energy landscape . . . . . . . . . . . . . . . . . . . . . . . . . 60
3.6 Characteristics of increasing oligomer size . . . . . . . . . . . . . . . . . . 62
3.7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
4 Simulation Results for A(10-35)-NH Monomers 692
4.1 Previous experimental and theoretical observations . . . . . . . . . . . . . 69
4.2 Setup for two different force fields and equilibration . . . . . . . . . . . . 71
4.3 Analysis of conformational clusters . . . . . . . . . . . . . . . . . . . . . . 72
4.4 Comparison with experimental NMR data . . . . . . . . . . . . . . . . . . 76
4.4.1 NOE distances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
3 α4.4.2 J N scalar coupling constants . . . . . . . . . . . . . . . . . . . 79H H
4.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
5 Simulation Results for A(10-35)-NH Dimers 852
5.1 Previous experimental and theoretical observations . . . . . . . . . . . . . 85
5.2 System setup and equilibration . . . . . . . . . . . . . . . . . . . . . . . . 86
5.3 Analysis of conformational clusters . . . . . . . . . . . . . . . . . . . . . . 87
5.4 Free energy landscape . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
5.5 Interactions stabilizing different dimer conformations . . . . . . . . . . . . 95
5.6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
6 Summary 101
A List of NOE distances A(10-35)-NH monomer 1052
4CONTENTS
B Dihedral angle distributions A