De Novo Peptide Design: Principles and Applications

List of contributors xiii


1. Structural organization of peptides 1
Kirtikumar Patel

1.1 Molecular interactions for protein folding 3

1.1.1 Hydrogen bonds 3

1.1.2 CH2 — π interactions 4

1.1.3 van der Waals interactions 4

1.1.4 Hydrophobic interaction 4

1.1.5 Electrostatic interactions 5

1.1.6 Aromatic — aromatic (π — π) interactions 5

1.1.7 Cation — π interaction 5

1.2 Poly-alanine models and the energetics of protein folding 6

1.3 De novo protein design and stereochemical logic of protein folding 8

1.3.1 Stereochemical principles in protein design 8

1.3.2 β-Turn as stereochemically diverse conformational nucleators 9

1.3.3 Design of β-sheet proteins 12

1.3.4 All α-helix protein design 15

1.3.5 Metalloprotein design 15

1.4 Shape-specific design of heterochiral proteins 16

1.5 Enzymes: functional proteins 17

1.5.1 Hydrolase enzymes 18

References 20


2. Modeling and simulation of peptides 35
Amay Redkar and Vibin Ramakrishnan

2.1 Introduction 35

2.2 Peptide design 36

2.2.1 Ligand-based peptide design 38

2.2.2 Target-based peptide design 40

2.2.3 De novo peptide design 41

2.3 Prediction of peptide structure 41

2.4 In silico validation of design by molecular dynamic simulations 42

2.4.1 Temperature and pressure coupling 43

2.4.2 Energy minimization 44

2.4.3 Force field 45

2.4.4 Conformational analysis 46

2.4.5 Case studies of molecular dynamics simulations and trajectory analysis 48

2.5 Conclusion 50

References 50


3. Solid phase peptide synthesis 57
Deepti Goyal and Bhupesh Goyal

3.1 Introduction 57

3.2 Principles of solid phase peptide synthesis 58

3.2.1 Merrifield solid phase peptide synthesis or Boc/Bzl 59

3.2.2 Fmoc/tBu solid phase peptide synthesis 60

3.3 Resins 61

3.4 Linkers 64

3.5 Side-chain protecting groups 64

3.6 Coupling reaction 65

3.7 Fmoc deprotection 70

3.8 Final cleavage 71

3.9 Side reactions 72

3.9.2 Aspartimide formation 72

References 73


4. Peptide-based Antibiotics 79
Ruchika Goyal and Vibin Ramakrishnan

4.1 Introduction 79

4.2 Antimicrobial peptides 80

4.3 De novo design of antimicrobial peptides 81

4.3.1 Unnatural amino acids 82

4.3.2 Cyclization 83

4.3.3 Chemical modifications 84

4.3.4 Conjugation to conventional antibiotics 86

4.3.5 Multivalent approach 86

4.3.6 Antimicrobial peptide mimics 87

4.4 Antimicrobial peptides: Strategy to combat antimicrobial resistance 87

4.5 Mechanism of action and selectivity of antimicrobial peptides 89

4.5.1 Barrel-stave model 91

4.5.2 Carpet model 92

4.5.3 Toroidal model 92

4.5.4 Disordered toroidal-pore model 92

4.6 Strengths and weakness of antimicrobial peptides 92

4.6.1 Merits of antimicrobial peptides 92

4.6.2 Limitations of antimicrobial peptides 93

4.7 Conclusion 93

References 93


5. Cell-penetrating peptides 105
Aparna Rai and Gaurav Jerath

5.1 Cell-penetrating peptides: a brief history 106

5.2 Classification of cell-penetrating peptides 108

5.2.1 Cationic cell-penetrating peptides 108

5.2.2 Amphipathic cell-penetrating peptides 109

5.3 Mechanism of uptake 110

5.3.1 Interaction with cell surface 111

5.3.2 Cellular internalization of cell-penetrating peptides 112

5.3.3 Cellular localization 115

5.3.4 Transcellular transport and degradation 116

5.4 Strengths, limitations, and opportunities 117

5.5 Cell-type specificity: to be or not to be 118

5.6 Cell-penetrating peptides for anticancer drug delivery 118

5.6.1 Cell-penetrating peptides for targeted delivery 119

5.6.2 Delivery of anticancer drugs using cell-penetrating peptides 119

5.7 Cell-penetrating peptide prediction 119

5.8 Designing cell-penetrating peptides 121

5.8.1 Amino acid sequence 121

5.8.2 Secondary structure folding and its effects on cellular uptake 122

5.9 Conclusion 123

References 123


Peptide-based nanomaterials: applications and challenges 133
Gaurav Pandey and Debika Datta

6.1 Introduction to molecular self-assembly 133

6.2 Protein and peptide self-assembly 135

6.3 Peptide-based nanomaterials 136

6.3.1 Amyloid peptides 142

6.3.2 Cyclic peptides 145

6.3.3 Peptide amphiphiles 145

6.3.4 Turn containing peptides 148

6.3.5 Aromatic-moiety containing peptides and amino acids 151

6.4 Applications of peptide-based nanomaterials 153

6.5 Conclusion, challenges, and future directions 155

References 156


7. Peptide nanocatalysts 173
Jahnu Saikia and Vibin Ramakrishnan

7.1 Introduction 173

7.2 Types of catalysts 174

7.2.1 Homogeneous catalysts 174

7.2.2 Heterogeneous catalysts 175

7.2.3 Nanocatalysts 176

7.3 Enantioselectivity in catalytic reactions 178

7.4 Enzyme catalysis 179

7.4.1 Enzyme active site 180

7.5 Enzyme mimetics 184

7.5.1 Single amino acid mutations can impart high catalytic activity onto a protein 185

7.5.2 Incorporation of unnatural amino acids as a minimalistic approach for enzyme design 186

7.5.3 De novo design of peptide-based enzyme mimics 186

7.5.4 Peptide-based minimalist approach of enzyme catalysis 187

7.6 Structural design of the artificial peptide-based enzyme 189

7.6.1 Optimization of the catalytic microenvironment 189

7.7 Self-assembling peptide catalysts 190

7.8 Peptide mimics with enhanced catalytic efficiency 191

7.9 Peptide-based artificial metalloenzyme 191

7.10 Exploring unnatural amino acids for de novo peptide-based metalloenzymes 193

7.11 Aldolase mimic 193

7.11.1 Metal ion-free aldolase mimic (Type I aldolases) 194

7.12 Hydrolase mimic 196

7.13 Oxidase mimic 197

7.13.1 Lytic polysaccharide monooxygenase 197

7.14 Conclusions and future prospects 198

References 199


8. Bioinspired functional molecular constructs 207
Vivek Prakash and Vibin Ramakrishnan

8.1 Introduction 207

8.2 Peptide-based functional materials 208

8.2.1 De novo designed fluorescent peptide 210

8.2.2 De novo designed antimicrobial peptides 211

8.2.3 De novo designed cell-penetrating and tumor homing peptide 213

8.2.4 De novo designed biocatalysts 215

8.2.5 Peptide-based smart materials 219

8.3 De novo designed peptide nano-assemblies 222

8.3.1 Nanotubes 222

8.3.2 Nanosheets 223

8.3.3 Cyclic peptides 223

8.3.4 Nanofibers 224

8.3.5 Hydrogels 224

8.4 Properties of self-assembled nanostructures 227

8.4.1 Mechanical properties 227

8.4.2 Electrical properties 228

8.4.3 Optical properties 228

8.5 Factors affecting nanoassemblies 229

8.5.1 Aromatic π — π interactions 229

8.5.2 Hydrogen bonding 230

8.5.3 Hydrophobic interactions 231

8.5.4 Electrostatic interactions 231

8.5.5 Van der Waals interactions 231

8.5.6 Solvent effects 232

8.6 Applications of de novo designed peptide constructs 232

8.6.1 Tissue engineering 233

8.6.2 Drug delivery systems 233

8.6.3 Antimicrobial peptide hydrogel for wound healing 234

8.6.4 Biosensors 236

8.7 Conclusion and future directions 236

References 237


9. Patents in peptide science 255
Mouli Sarkar and Ranjit Ranbhor

9.1 Introduction 255

9.2 Basics of protein and peptide structure 255

9.2.1 Patents 256

9.3 Modeling and simulation of peptides 257

9.3.1 Patents 257

9.4 Glucagon-like peptide-1 analogs 258

9.4.1 Patents 258

9.5 Peptide-based antibiotics 260

9.5.1 Patents 260

9.6 Drug delivery vehicles 262

9.6.1 Patents 263

9.7 Protein aggregation 265

9.7.1 Patents 265

9.8 Peptide nanomaterials 266

9.8.1 Patents 266

9.9 Peptide-based hydrogels 267

9.9.1 Patents 267

9.10 Therapeutic interventions against protein/peptide aggregation diseases 269

9.10.1 Patents 269

9.11 Computational tools and algorithms in peptide design 270

9.11.1 Patents 271

References 271


Index 277