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From peptide chains to chains of peptides: multiscale modelling of self-assembling fibril-forming polypeptides - Contents

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From peptide chains to chains of peptides: multiscale modelling of

self-assembling fibril-forming polypeptides

Schor, M.

Publication date

2011

Link to publication

Citation for published version (APA):

Schor, M. (2011). From peptide chains to chains of peptides: multiscale modelling of

self-assembling fibril-forming polypeptides. Ipskamp Drukkers B.V.

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Contents

1 Introduction 9

1.1 Exploiting Self-Assembly . . . 9

1.2 Natural Amyloids . . . 10

1.3 Amyloid-like Fibril Structure . . . 12

1.4 Fibril Formation . . . 14

1.5 Amyloid Fibrils as Novel Nanomaterials . . . 17

1.6 Aims and Outline of this Thesis . . . 18

2 Simulation Methods 21 2.1 Molecular Dynamics . . . 21

2.2 Atomistic Force Fields . . . 23

2.3 Coarse-graining . . . 25

2.4 Lattice Models . . . 26

2.5 Free Energy Methods . . . 27

2.5.1 Umbrella Sampling . . . 29

2.5.2 Steered MD . . . 29

2.5.3 Replica Exchange . . . 31

2.6 Transition Path Sampling . . . 33

2.6.1 Defining Stable States . . . 33

2.6.2 Generating and Accepting New Pathways . . . 34

2.6.3 Reaction coordinate analysis . . . 35

I Fibril Formation of Silk-based Block Copolymers 37 3 Prediction of Solvent-dependent β-roll Formation of a Self-assembling Silk-like Pro-tein Domain 39 3.1 Introduction . . . 39

3.2 Methods . . . 42

3.3 Results and Discussion . . . 43

3.3.1 Structure Construction of the Silk-like Block . . . 43

3.3.2 Assessing Thermodynamic Stability in Water by REMD Simulation . . . . 46

3.3.3 Assessing Thermodynamic Stability in Methanol . . . 51 5

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3.3.4 The Hydrophobic Effect . . . 51

3.4 Conclusions . . . 53

4 A Simple Coarse-grained Model for Silk-based Block Copolymers 55 4.1 Introduction . . . 55

4.2 Simulation Details . . . 57

4.3 Model Development . . . 58

4.3.1 Adapting the Head-Gordon Model . . . 58

4.3.2 Fitting Distributions from Atomistic Simulation . . . 59

4.3.3 Matching Coarse-grained and Atomistic PMFs . . . 62

4.4 Coarse-grained Simulation of the β roll and Large Stacks . . . 65

4.5 Extension of the Force Field to Include the Hydrophylic Blocks . . . 68

4.6 Discussion and Conclusions . . . 70

5 Self-Assembly Mechanism of Fibril-forming Silk-based Block Copolymers 71 5.1 Introduction . . . 71

5.2 Methods . . . 74

5.2.1 All-atom Simulations . . . 74

5.2.2 Coarse-grained Simulations . . . 75

5.3 Results and Discussion . . . 76

5.3.1 Self-assembly Behaviour of Silk-based Blocks . . . 76

5.3.2 Effect of the Hydrophilic Blocks on Self-assembly . . . 82

5.4 Conclusions . . . 85

6 Folding versus Assembly of a Silk-based Peptide 89 6.1 Introduction . . . 89

6.2 Methods . . . 91

6.2.1 3D Lattice Model . . . 91

6.2.2 Simulation Details . . . 95

6.3 Results and Discussion . . . 96

6.3.1 Design of the Polypeptide Sequence . . . 96

6.3.2 Effect of Alanine Hydrophobicity on Folding and Aggregation . . . 98

6.3.3 Effect of Hydrophilic Tails on Folding and Aggregation . . . 103

6.4 Conclusions . . . 107

II Dynamics of Fibril Growth 111 7 Elucidating the Locking Mechanism of Peptides onto Growing Amyloid Fibrils through Transition Path Sampling 113 7.1 Introduction . . . 113

7.2 Simulation Details . . . 115

7.3 Results and Discussion . . . 116

7.3.1 Simulating the Locked State . . . 116 6

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7.3.2 Steered MD Simulations . . . 118 7.3.3 TPS Simulations of Incorporation of Peptide Monomers into the Fibril . . 119 7.4 Conclusions . . . 126 Bibliography 129 Abbreviations 141 Summary 143 Samenvatting 147 Publications 151 Curriculum vitea 153 Bedankt! 155 7

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