Foreword ................................................... V
Preface ................................................... XV
List of Contributors ..................................... XIX
Part 1 Structure: Foldamer Design Concepts ..................... 1
1 Foldamers Based on Local Conformational Preferences ........ 3
Ivan Hue and Louis Cuccia
1.1 Introduction ............................................... 3
1.2 Rigidly Locked Molecules ................................... 4
1.3 Predictable Foldamers ...................................... 5
1.3.1 Local Conformational Control ........................ 6
1.3.2 Folded Conformations of π-conjugated Systems ........ 9
1.3.3 Partially π-conjugated Oligomers ................... 16
1.4 Semi-rigid Backbones ...................................... 17
1.4.1 Tertiary Aromatic Amides, Imides and Ureas ......... 18
1.4.2 Tertiary Aliphatic Amides: Polyprolines and
Peptoids ........................................... 20
1.4.3 Hindered Polymer and Oligomer Backbones ............ 23
1.5 Conformational Transitions ................................ 25
1.6 Conclusion and Perspectives ............................... 27
References ................................................ 28
2 Foldamers Based on Remote Intrastrand Interactions ........ 35
Philippe Le Crel and Cities Guichard
2.1 Introduction .............................................. 35
2.2 What can be Learned from Strategies used to Control
Conformations of α-Polypeptides? .......................... 36
2.3 Helices from Homogeneous Oligomeric Backbones with
Periodicity at the Monomer Level: ω-Peptides and their
Analogs ................................................... 37
2.3.1 Compact Helices with Large (>10 atoms) H-bonded
Rings .............................................. 37
2.3.2 Extended Helices with Small H-bonded Rings
Centered at a Single Residue ....................... 45
2.4 Oligoamide Mixed Helices .................................. 51
2.4.1 The α-Oligopeptide Precedent: from Antibiotic
Gramicidin A to Poly-Gin Aggregates in
Huntington's Disease ............................... 52
2.4.2 Introducing Periodicity at the Level of a Dimer
Unit in β-Peptides leads to a Remarkably Stable
Mixed Helical Fold ................................. 53
2.4.3 Extending the Concept of Mixed Helices ............. 56
2.5 Nonperiodic Structures: Open Chain β-Turn-like Motifs
and Hairpins in Designed Homo-oligomers ................... 58
2.5.1 Sheet-forming ω-peptides ........................... 58
2.5.2 Turn Segment for Hairpin Formation ................. 59
2.6 Expanding Structural Diversity with Heterogeneous
Backbones ................................................. 61
2.6.1 From Discrete γ-Amino Acid Guests in α-Helices
to Helical α, ω- and β,γ-Peptide Hybrids ........... 61
2.6.2 Hairpins from α, ω-Peptide Hybrids ................. 65
2.6.3 Sculpting New Shapes by Integrating H-Bonding,
Aromatic Interactions and Multiple Levels of
Pre-organization ................................... 66
2.7 Conclusion and Outlook .................................... 67
References ................................................ 68
3 Foldamers Based on Solvophobic Effects .................... 75
Yan Zhao and Jeffrey S. Moore
3.1 Introduction .............................................. 75
3.2 Learning from Solvophobically Driven Assemblies -
Intermolecular Solvophobic Interactions ................... 77
3.3 Learning from Synthetic and Biological Polymers ........... 81
3.4 Recent Advances in Foldamers Based on Solvophobic
Effects ................................................... 84
3.4.1 Foldamers Stabilized by Adjacent, Identical
Aromatic Units ..................................... 85
3.4.2 Foldamers Stabilized by Adjacent Donor-acceptor
Aromatic Units ..................................... 87
3.4.3 Foldamers Stabilized by Nonadjacent Aromatic
Units .............................................. 92
3.4.4 Foldamers Stabilized by Aliphatic Units ........... 100
3.5 Conclusions and Outlook .................................. 103
References ............................................... 104
4 Foldamer Hybrids: Defined Supramolecular Structures
from Flexible Molecules .................................. 109
Carsten Schmuck and Thomas Rehm
4.1 Introduction ............................................. 109
4.2 Hybridization of Oligomers with Well-defined Structures .. 112
4.2.1 Coiled Coils and Helix Bundles .................... 112
4.2.2 Intertwined Strands ............................... 116
4.2.3 Stacks of Helical Strands and Macrocycles ......... 117
4.2.4 Tapes and Hydrogen-bonded Sheets .................. 120
4.3 Hybridization-induced Folding of Unstructured Molecules .. 122
4.3.1 Hydrogen-bonded Tapes ............................. 122
4.3.2 Helices Based on Metal-ligand Interactions and
Salt Bridges ...................................... 127
4.3.3 Double-stranded Hybrids Based on Aryl-aryl
Interactions and Hydrophobic Contacts ............. 130
4.3.4 Hybrids Based on DNA-base-pairing Recognition ..... 132
4.4 Formation of Large Polymeric Aggregates via
Self-assembly ............................................ 136
4.5 Applications of Foldamer Hybridization ................... 139
4.6 Conclusion ............................................... 143
References ............................................... 143
5 Control of Polypeptide Chain Folding and Assembly ........ 147
Rajkishor Rai and Padmanabhan Balaram
5.1 Introduction ............................................. 147
5.2 Helix Promotion by Backbone Substitution ................. 150
5.2.1 α-Aminoisobutyric Acid (Aib) and Related Dialkyl
Amino Acids ....................................... 150
5.2.2 Diproline Segments ................................ 152
5.3 Hairpin Design using Obligatory Turn Segments ............ 155
5.3.1 DPro-Xxx Turns .................................... 155
5.3.2 Aib-DXxx Turns .................................... 357
5.3.3 Asn-Gly Turns ..................................... 159
5.3.4 Expanded Loop Segments ............................ 161
5.3.5 Choice of Strand Residues ......................... 161
5.4 Helix-Helix Motifs ....................................... 162
5.5 Multi-stranded β-Sheets .................................. 164
5.6 Mixed Helix-Sheet (α/β) Structures ....................... 165
5.7 Conclusions .............................................. 367
References ............................................... 168
6 Simulation of Folding Equilibria ......................... 173
Wilfred F. van Cunsteren and Zrinka Cattin
6.1 Introduction ............................................. 173
6.2 Dynamical Simulation of Folding Equilibria under
Different Thermodynamic and Kinetic Conditions ........... 175
6.3 Variation of the Composition of the Polypeptide Analogs
and the Solvent .......................................... 178
6.4 Convergence of the Simulated Folding Equilibrium ......... 181
6.5 Sensitivity of the Folding Equilibrium to the Force
Field Used ............................................... 184
6.6 Comparison of Simulated with Experimentally Measured
Observables .............................................. 185
6.7 Characterization of the Unfolded State and the Folding
Process .................................................. 186
6.8 Conclusion ............................................... 190
References ............................................... 190
Part 2 Function: From Properties to Applications ............. 193
7 Foldamer-based Molecular Recognition ..................... 195
Jorge Becerril, Johanna M. Rodriguez, Ishu Saraogi and
Andrew D. Hamilton
7.1 Introduction ............................................. 195
7.2 Small Molecule Recognition Using Foldamers ............... 396
7.2.1 Receptors for Water Molecules ..................... 396
7.2.2 Receptors for Ammonium Cations .................... 198
7.2.3 Receptors for Hydrophobic Small Molecules ......... 201
7.2.4 Receptors for Saccharides ......................... 204
7.2.5 Receptors of Other Organic Molecules .............. 207
7.3 Protein Recognition ...................................... 230
7.3.1 Abiotic Synthetic Foldamers ....................... 233
7.3.2 Peptidomimetic Foldamers .......................... 232
7.4 Mimicry of Biomineralization: Recognition of Crystal
Surfaces Using Foldamers ................................. 217
7.4.1 Introduction to Biomineralization ................. 237
7.4.2 Biomimetic Synthesis of Calcite Using Foldamers ... 220
7.4.3 Biomimetic Synthesis of CdS Using Foldamers ....... 224
7.5 Conclusion ............................................... 224
References ............................................... 225
8 Biological Applications of Foldamers ..................... 229
Marc Koyack and Richard Cheng
8.1 Introduction ............................................. 229
8.1.1 β-Peptides ........................................ 230
8.1.2 Peptoids .......................................... 231
8.1.3 Peptide Nucleic Acids (PNA) ....................... 233
8.1.4 DNA-Binding Oligoamides ........................... 232
8.1.5 Aryl Amides and Aryl Ureas ........................ 234
8.1.6 meta-Phenylene Ethynylenes (mPE) .................. 235
8.1.7 Terphenyls ........................................ 235
8.2 Design Strategies ........................................ 236
8.2.1 Direct Sequence Conversion ........................ 237
8.2.2 Distribution of Physicochemical Properties ........ 240
8.2.3 Modular Assembly .................................. 248
8.2.4 Grafting Bioactive Functionalities onto
Scaffolds ......................................... 253
8.3 Outlook and Future Directions ............................ 257
References ............................................... 257
9 Protein Design ........................................... 267
Jean-Luc Jestin and Frédéric Pecorari
9.1 Introduction ............................................. 267
9.2 Design of Proteins from Natural Scaffolds ................ 269
9.2.1 Design of Enzymes ................................. 270
9.2.2 Design of Binding Proteins ........................ 272
9.3 Design of Proteins from Building Blocks .................. 275
9.3.1 Design of Proteins from Structural Domains ........ 275
9.3.2 Design of Proteins from Secondary Structures ...... 277
9.4 Design of Proteins using Altered Alphabets ............... 280
9.4.1 Design of Proteins using Reduced Alphabets ........ 280
9.4.2 Design of Proteins using Extended Alphabets ....... 281
9.5 Design of Proteins de novo ............................... 284
9.5.1 Computational Design of New Folds and
Experimental Proofs ............................... 284
9.5.2 Combinatorial and Experimental Design ............. 284
9.6 Conclusion ............................................... 286
References ............................................... 287
10 Nucleic Acid Foldamers: Design, Engineering and
Selection of Programmable Biomaterials with
Recognition, Catalytic and Self-assembly Properties ...... 291
Arkadiusz Chworos and Luc Jaeger
10.1 Introduction ............................................. 291
10.2 Principles of Nucleic Acid Foldamers ..................... 292
10.2.1 Structural Principles: Hierarchical Organization
and Modularity .................................... 292
10.3 Synthesis of Nucleic Acid Foldamers and Analogs .......... 303
10.4 Combinatorial Approaches for Isolating Functional
Nucleic Acid Foldamers ................................... 306
10.5 DNA Architectonics ....................................... 307
10.5.1 Rational Design of DNA Tiles ...................... 308
10.5.2 Principle of Tensegrity and Mode of Assembly ...... 309
10.6 RNA Architectonics ....................................... 310
10.6.1 General Approach .................................. 310
10.6.2 Examples of RNA Nano-architectures ................ 313
10.7 Self-assembly Strategies for Building Complex Nucleic
Acid Nanostractures ...................................... 315
10.7.1 Programmable Self-assembly ........................ 315
10.8 Ornamentation and Functionalization of Nucleic Acid
Architectures ............................................ 319
10.8.1 General Principles ................................ 319
10.8.2 Nucleic Acid Foldamers for Sensors, Medicine and
Nano-electronics .................................. 319
10.9 Conclusions .............................................. 321
References ............................................... 323
11 Helically Folding Polymers ............................... 331
Eiji Yashima and Katsuhiro Maeda
11.1 Introduction ............................................. 331
11.2 Helical Polymers with High Helix Inversion Barriers
(Static Helical Polymers) ................................ 332
11.2.1 Poly(triarylmethyl methacrylate)s ................. 333
11.2.2 Polychloral ....................................... 334
11.2.3 Polyisocyanides ................................... 336
11.2.4 Polyguanidines .................................... 337
11.3 Helical Polymers with Low Helix Inversion Barriers
(Dynamic Helical Polymers) ............................... 338
11.3.1 Dynamic Helical Polymers Assisted by Covalent
Bonding ........................................... 339
11.3.2 Dynamic Helical Polymers Assisted by Noncovalent
Bonding ........................................... 344
11.3.3 Memory of Induced Helical Chirality ............... 351
11.4 Inversion of Macromolecular Helicity ..................... 355
11.5 Applications of Helical Polymers ......................... 359
11.6 Conclusion ............................................... 362
References ............................................... 363
12 Polyisocyanides: Stiffened Foldamers ..................... 367
Matthijs B.J. Otten, Ceroid A. Metselaar, Jeroen
J.L.M. Cornelissen, Alan E. Rowan and Roeland
J.M. Nolte
12.1 Introduction ............................................. 367
12.2 Preparation .............................................. 368
12.3 Conformation ............................................. 370
12.4 Stiffening the Helix ..................................... 377
12.5 Functionalized Polyisocyanides ........................... 387
12.6 Conclusions .............................................. 398
References ............................................... 398
13 Foldamers at Interfaces .................................. 403
Jan van Esch, Hennie Valkenier, Sebastian Hartwig, and
Stefan Hecht
13.1 Introduction ............................................. 403
13.2 Folding in Solution and at Interfaces .................... 405
13.2.1 Types of Interactions ............................. 406
13.2.2 Thermodynamics .................................... 406
13.2.3 Design Considerations ............................. 408
13.2.4 Scope ............................................. 409
13.3 Helical Structures ....................................... 410
13.3.1 Adsorption of Helical Structures at Interfaces .... 410
13.3.2 Loss of Helicity upon Adsorption .................. 412
13.3.3 Helical Structures Formed upon Adsorption ......... 414
13.4 Sheet Structures ......................................... 415
13.4.1 Adsorbed Sheet Structures at Interfaces ........... 415
13.4.2 Enhanced Sheet Formation upon Adsorption .......... 417
13.4.3 Change in Sheet Structure upon Adsorption ......... 420
13.5 Turn Elements and Hairpins ............................... 421
13.6 Outlook .................................................. 423
References ............................................... 424
Index .................................................... 427
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