Foreword 7
Contents 9
Preface 17
List of Contributors 21
Part 1 Structure: Foldamer Design Concepts 25
1 Foldamers Based on Local Conformational Preferences 27
1.1 Introduction 27
1.2 Rigidly Locked Molecules 28
1.3 Predictable Foldamers 29
1.3.1 Local Conformational Control 30
1.3.2 Folded Conformations of 蟺-conjugated Systems 33
1.3.2.1 Crescents and Helices 33
1.3.2.2 Linear Strands 37
1.3.2.3 Macrocycles 37
1.3.3 Partially 蟺-conjugated Oligomers 40
1.4 Semi-rigid Backbones 41
1.4.1 Tertiary Aromatic Amides, Imides and Ureas 42
1.4.2 Tertiary Aliphatic Amides: Polyprolines and Peptoids 44
1.4.3 Hindered Polymer and Oligomer Backbones 47
1.5 Conformational Transitions 49
1.6 Conclusion and Perspectives 51
References 52
2 Foldamers Based on Remote Intrastrand Interactions 59
2.1 Introduction 59
2.2 What can be Learned from Strategies used to Control Conformations of 伪-Polypeptides? 60
2.3 Helices from Homogeneous Oligomeric Backbones with Periodicity at the Monomer Level: 蠅-Peptides and their Analogs 61
2.3.1 Compact Helices with Large (>10 atoms) H-bonded Rings 61
2.3.1.1 The Homologation Strategy: 尾- and 纬-Peptide Foldamers 61
2.3.1.2 Imposing Backbone Conformational Restriction/Pre-organization for Optimal Helical Folding 63
2.3.1.3 Folding in an Aqueous Environment 67
2.3.1.4 Dynamics of 尾- and 纬-Peptide Helices: Evidence for Noncooperative Folding/Unfolding Processes 68
2.3.2 Extended Helices with Small H-bonded Rings Centered at a Single Residue 69
2.3.2.1 伪-Peptides: the 纬-Helix 69
2.3.2.2 蠅-Peptides with Specific Conformation-stabilizing Elements 69
2.3.2.3 Stabilizing Local Backbone Conformation by Inverse-Bifurcation Involving an Additional Heteroatom 72
2.4 Oligoamide Mixed Helices 75
2.4.1 The 伪-Oligopeptide Precedent: from Antibiotic Gramicidin A to Poly-Gln Aggregates in Huntington\u2019s Disease 76
2.4.2 Introducing Periodicity at the Level of a Dimer Unit in 尾-Peptides leads to a Remarkably Stable Mixed Helical Fold 77
2.4.2.1 By Mixing 尾(2)- and 尾(3)-Amino Acids 77
2.4.2.2 Additional Substitution Patterns Stabilizing the Mixed 10/12- (12/10-) Helix 79
2.4.3 Extending the Concept of Mixed Helices 80
2.5 Nonperiodic Structures: Open Chain 尾-Turn-like Motifs and Hairpins in Designed Homo-oligomers 82
2.5.1 Sheet-forming 蠅-peptides 82
2.5.2 Turn Segment for Hairpin Formation 83
2.6 Expanding Structural Diversity with Heterogeneous Backbones 85
2.6.1 From Discrete 蠅-Amino Acid Guests in 伪-Helices to Helical 伪,蠅- and 尾,纬-Peptide Hybrids 85
2.6.2 Hairpins from 伪,蠅-Peptide Hybrids 89
2.6.3 Sculpting New Shapes by Integrating H-Bonding, Aromatic Interactions and Multiple Levels of Pre-organization 90
2.7 Conclusion and Outlook 91
References 92
3 Foldamers Based on Solvophobic Effects 99
3.1 Introduction 99
3.2 Learning from Solvophobically Driven Assemblies \u2013 Intermolecular Solvophobic Interactions 101
3.3 Learning from Synthetic and Biological Polymers 105
3.4 Recent Advances in Foldamers Based on Solvophobic Effects 108
3.4.1 Foldamers Stabilized by Adjacent, Identical Aromatic Units 109
3.4.2 Foldamers Stabilized by Adjacent Donor\u2013acceptor Aromatic Units 111
3.4.3 Foldamers Stabilized by Nonadjacent Aromatic Units 116
3.4.4 Foldamers Stabilized by Aliphatic Units 124
3.5 Conclusions and Outlook 127
References 128
4 Foldamer Hybrids: Defined Supramolecular Structures from Flexible Molecules 133
4.1 Introduction 133
4.2 Hybridization of Oligomers with Well-defined Structures 136
4.2.1 Coiled Coils and Helix Bundles 136
4.2.2 Intertwined Strands 140
4.2.3 Stacks of Helical Strands and Macrocycles 141
4.2.4 Tapes and Hydrogen-bonded Sheets 144
4.3 Hybridization-induced Folding of Unstructured Molecules 146
4.3.1 Hydrogen-bonded Tapes 146
4.3.2 Helices Based on Metal-ligand Interactions and Salt Bridges 151
4.3.3 Double-stranded Hybrids Based on Aryl-aryl Interactions and Hydrophobic Contacts 154
4.3.4 Hybrids Based on DNA-base-pairing Recognition 156
4.4 Formation of Large Polymeric Aggregates via Self-assembly 160
4.5 Applications of Foldamer Hybridization 163
4.6 Conclusion 167
References 167
5 Control of Polypeptide Chain Folding and Assembly 171
5.1 Introduction 171
5.2 Helix Promotion by Backbone Substitution 174
5.2.1 伪-Aminoisobutyric Acid (Aib) and Related Dialkyl Amino Acids 174
5.2.2 Diproline Segments 176
5.3 Hairpin Design using Obligatory Turn Segments 179
5.3.1 (D)Pro-Xxx Turns 179
5.3.2 Aib-(D)Xxx Turns 181
5.3.3 Asn-Gly Turns 183
5.3.4 Expanded Loop Segments 185
5.3.5 Choice of Strand Residues 185
5.4 Helix\u2013Helix Motifs 186
5.5 Multi-stranded 尾-Sheets 188
5.6 Mixed Helix-Sheet (伪/尾) Structures 189
5.7 Conclusions 191
References 192
6 Simulation of Folding Equilibria 197
6.1 Introduction 197
6.2 Dynamical Simulation of Folding Equilibria under Different Thermodynamic and Kinetic Conditions 199
6.3 Variation of the Composition of the Polypeptide Analogs and the Solvent 202
6.4 Convergence of the Simulated Folding Equilibrium 205
6.5 Sensitivity of the Folding Equilibrium to the Force Field Used 208
6.6 Comparison of Simulated with Experimentally Measured Observables 209
6.7 Characterization of the Unfolded State and the Folding Process 210
6.8 Conclusion 214
References 214
Part 2 Function: From Properties to Applications 217
7 Foldamer-based Molecular Recognition 219
7.1 Introduction 219
7.2 Small Molecule Recognition Using Foldamers 220
7.2.1 Receptors for Water Molecules 220
7.2.2 Receptors for Ammonium Cations 222
7.2.3 Receptors for Hydrophobic Small Molecules 225
7.2.4 Receptors for Saccharides 228
7.2.5 Receptors of Other Organic Molecules 231
7.3 Protein Recognition 234
7.3.1 Abiotic Synthetic Foldamers 235
7.3.2 Peptidomimetic Foldamers 236
7.4 Mimicry of Biomineralization: Recognition of Crystal Surfaces Using Foldamers 241
7.4.1 Introduction to Biomineralization 241
7.4.2 Biomimetic Synthesis of Calcite Using Foldamers 244
7.4.3 Biomimetic Synthesis of CdS Using Foldamers 248
7.5 Conclusion 248
References 249
8 Biological Applications of Foldamers 253
8.1 Introduction 253
8.1.1 尾-Peptides 254
8.1.2 Peptoids 255
8.1.3 Peptide Nucleic Acids (PNA) 255
8.1.4 DNA-Binding Oligoamides 256
8.1.5 Aryl Amides and Aryl Ureas 258
8.1.6 meta-Phenylene Ethynylenes (mPE) 259
8.1.7 Terphenyls 259
8.2 Design Strategies 260
8.2.1 Direct Sequence Conversion 261
8.2.1.1 RNA-binding Peptoids 261
8.2.1.2 RNA-binding Oligourea and Carbamate 262
8.2.1.3 RNA-binding 尾-Peptides 263
8.2.1.4 Receptor-binding 尾-Peptides 263
8.2.2 Distribution of Physicochemical Properties 264
8.2.2.1 Antimicrobial Peptoids 264
8.2.2.2 Antimicrobial 尾-Peptides 265
8.2.2.3 Antimicrobial Aryl Amides and Aryl Ureas 267
8.2.2.4 Antimicrobial meta-Phenylene Ethynylenes 268
8.2.2.5 DNA-binding Peptoids 268
8.2.2.6 DNA-binding 尾-Peptides 269
8.2.2.7 Cholesterol Uptake-inhibiting 尾-Peptides 269
8.2.2.8 Heparin-inhibiting Aryl Amides 271
8.2.2.9 Calmodulin-inhibiting Aryl Amides 272
8.2.3 Modular Assembly 272
8.2.3.1 DNA-binding Oligoamides 272
8.2.3.2 Nucleotide-binding Peptide Nucleic Acids 275
8.2.4 Grafting Bioactive Functionalities onto Scaffolds 277
8.2.4.1 Protein\u2013protein Interaction-inhibiting 尾-Peptides 277
8.2.4.2 Protein\u2013protein Interaction-inhibiting Peptoids 279
8.2.4.3 Terphenyl Helix Mimetics 280
8.3 Outlook and Future Directions 281
References 281
9 Protein Design 291
9.1 Introduction 291
9.2 Design of Proteins from Natural Scaffolds 293
9.2.1 Design of Enzymes 294
9.2.1.1 Grafting Catalytic Sites in Proteins 294
9.2.1.2 Endowing Enzymes with Two Catalytic Activities in a Single Domain 294
9.2.1.3 Grafting Allosteric Sites to Regulate Enzyme Activity 295
9.2.2 Design of Binding Proteins 296
9.3 Design of Proteins from Building Blocks 299
9.3.1 Design of Proteins from Structural Domains 299
9.3.1.1 Methods for the Identification of Stable Structural Domains 299
9.3.1.2 Identifying New Folds and New Topologies 300
9.3.1.3 Combining Domains 301
9.3.2 Design of Proteins from Secondary Structures 301
9.4 Design of Proteins using Altered Alphabets 304
9.4.1 Design of Proteins using Reduced Alphabets 304
9.4.2 Design of Proteins using Extended Alphabets 305
9.4.2.1 By Codon Reassignment Strategies 306
9.4.2.2 By Suppression Strategies 306
9.5 Design of Proteins de novo 308
9.5.1 Computational Design of New Folds and Experimental Proofs 308
9.5.2 Combinatorial and Experimental Design 308
9.6 Conclusion 310
References 311
10 Nucleic Acid Foldamers: Design, Engineering and Selection of Programmable Biomaterials with Recognition, Catalytic and Self-assembly Properties 315
10.1 Introduction 315
10.2 Principles of Nucleic Acid Foldamers 316
10.2.1 Structural Principles: Hierarchical Organization and Modularity 316
10.2.1.1 Chemical Modularity and Stability 316
10.2.1.2 Secondary Structure Principles 318
10.2.1.3 Tertiary Structure Principles 319
10.2.1.4 Quaternary Structure Principles 322
10.2.2 Functional Principles: Recognition, Switches and Catalysis 323
10.2.2.1 Aptamers and Nucleic Acid Switches 325
10.2.2.2 Ribozymes and DNAzymes 326
10.2.2.3 Multifunctional Nucleic Acid Foldamers 326
10.3 Synthesis of Nucleic Acid Foldamers and Analogs 327
10.4 Combinatorial Approaches for Isolating Functional Nucleic Acid Foldamers 330
10.5 DNA Architectonics 331
10.5.1 Rational Design of DNA Tiles 332
10.5.2 Principle of Tensegrity and Mode of Assembly 333
10.6 RNA Architectonics 334
10.6.1 General Approach 334
10.6.2 Examples of RNA Nano-architectures 337
10.7 Self-assembly Strategies for Building Complex Nucleic Acid Nanostructures 339
10.7.1 Programmable Self-assembly 339
10.7.1.1 General Principles: \ 339
10.7.1.2 Addressable Self-assembly 341
10.7.1.3 Algorithmic Self-assembly 341
10.7.1.4 Templated Self-assembly and Scaffolded DNA Origami 341
10.7.2 Additional Principles of Nucleic Acid Architectonics 342
10.7.2.1 Principle of Orientational Compensation 342
10.7.2.2 Applications of Principles of Symmetry 342
10.7.2.3 Fractal Nano-architectures 342
10.8 Ornamentation and Functionalization of Nucleic Acid Architectures 343
10.8.1 General Principles 343
10.8.2 Nucleic Acid Foldamers for Sensors, Medicine and Nano-electronics 343
10.9 Conclusions 345
References 347
11 Helically Folding Polymers 355
11.1 Introduction 355
11.2 Helical Polymers with High Helix Inversion Barriers (Static Helical Polymers) 356
11.2.1 Poly(triarylmethyl methacrylate)s 357
11.2.2 Polychloral 358
11.2.3 Polyisocyanides 360
11.2.4 Polyguanidines 361
11.3 Helical Polymers with Low Helix Inversion Barriers (Dynamic Helical Polymers) 362
11.3.1 Dynamic Helical Polymers Assisted by Covalent Bonding 363
11.3.1.1 Polyisocyanates 363
11.3.1.2 Polysilanes 365
11.3.1.3 Polyacetylenes 366
11.3.2 Dynamic Helical Polymers Assisted by Noncovalent Bonding 368
11.3.2.1 Induced Helical Poly(phenylacetylene)s 369
11.3.2.2 Hierarchical Amplification of Helical-Sense Excess in Liquid Crystals 371
11.3.2.3 Other Induced Helical Polymers 373
11.3.3 Memory of Induced Helical Chirality 375
11.4 Inversion of Macromolecular Helicity 379
11.5 Applications of Helical Polymers 383
11.6 Conclusion 386
References 387
12 Polyisocyanides: Stiffened Foldamers 391
12.1 Introduction 391
12.2 Preparation 392
12.3 Conformation 394
12.4 Stiffening the Helix 401
12.5 Functionalized Polyisocyanides 411
12.6 Conclusions 422
References 422
13 Foldamers at Interfaces 427
13.1 Introduction 427
13.2 Folding in Solution and at Interfaces 429
13.2.1 Types of Interactions 430
13.2.2 Thermodynamics 430
13.2.3 Design Considerations 432
13.2.4 Scope 433
13.3 Helical Structures 434
13.3.1 Adsorption of Helical Structures at Interfaces 434
13.3.2 Loss of Helicity upon Adsorption 436
13.3.3 Helical Structures Formed upon Adsorption 438
13.4 Sheet Structures 439
13.4.1 Adsorbed Sheet Structures at Interfaces 439
13.4.2 Enhanced Sheet Formation upon Adsorption 441
13.4.3 Change in Sheet Structure upon Adsorption 444
13.5 Turn Elements and Hairpins 445
13.6 Outlook 447
References 448
Index 451