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Multivalency: Concepts, Research and Applications

Jurriaan Huskens (Editor), Leonard Prins (Editor), Rainer Haag (Editor), Bart Jan Ravoo (Editor), E. W. Meijer (Foreword by)
ISBN: 978-1-119-14346-8
416 pages
January 2018
Multivalency: Concepts, Research and Applications (1119143462) cover image


Connects fundamental knowledge of multivalent interactions with current practice and state-of-the-art applications 

Multivalency is a widespread phenomenon, with applications spanning supramolecular chemistry, materials chemistry, pharmaceutical chemistry and biochemistry. This advanced textbook provides students and junior scientists with an excellent introduction to the fundamentals of multivalent interactions, whilst expanding the knowledge of experienced researchers in the field.

Multivalency: Concepts, Research & Applications is divided into three parts. Part one provides background knowledge on various aspects of multivalency and cooperativity and presents practical methods for their study. Fundamental aspects such as thermodynamics, kinetics and the principle of effective molarity are described, and characterisation methods, experimental methodologies and data treatment methods are also discussed. Parts two and three provide an overview of current systems in which multivalency plays an important role in chemistry and biology, with a focus on the design rules, underlying chemistry and the fundamental principles of multivalency. The systems covered range from chemical/materials-based ones such as dendrimers and sensors, to biological systems including cell recognition and protein binding. Examples and case studies from biochemistry/bioorganic chemistry as well as synthetic systems feature throughout the book.

  • Introduces students and young scientists to the field of multivalent interactions and assists experienced researchers utilising the methodologies in their work
  • Features examples and case studies from biochemistry/bioorganic chemistry, as well as synthetic systems throughout the book
  • Edited by leading experts in the field with contributions from established scientists

Multivalency: Concepts, Research & Applications is recommended for graduate students and junior scientists in supramolecular chemistry and related fields, looking for an introduction to multivalent interactions. It is also highly useful to experienced academics and scientists in industry working on research relating to multivalent and cooperative systems in supramolecular chemistry, organic chemistry, pharmaceutical chemistry, chemical biology, biochemistry, materials science and nanotechnology.

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Table of Contents

List of Contributors xi

Foreword xv

Preface xvii

Part I General Introduction to Multivalent Interactions 1

1 Additivity of Energy Contributions in Multivalent Complexes 3
Hans -Jorg Schneider

1.1 Introduction 3

1.2 Additivity of Single Interactions – Examples 3

1.3 Limitations of Additivity 7

1.3.1 Free Energy Values ΔG Instead of Enthalpic and Entropic Values ΔH, TΔS 7

1.3.2 Mismatch as Limitation of Additivity 9

1.3.3 Medium Effects as Limiting Factor 12

1.3.4 Strain and Induced Fit 12

1.4 Cooperativity 13

1.5 Allostery 14

1.6 Conclusions 17

References 18

2 Models and Methods in Multivalent Systems 23
Jurriaan Huskens

2.1 Introduction 23

2.1.1 General Introduction 23

2.1.2 Multivalent versus Cooperative Interactions 24

2.2 Numerical Data Analysis 25

2.2.1 Model Simulations Using a Spreadsheet Approach 26

2.2.2 Setting Up and Assessing Titrations 30

2.2.3 Using Spreadsheet Simulations to Fit Experimental Data to a Model 36

2.3 Models for Multivalent Systems 41

2.3.1 The Simplest Multivalent System: A 1:1 Complex with Two Interaction Sites 41

2.3.2 Multivalent Binding at Surfaces 46

2.4 Special Multivalent Systems 53

2.4.1 Increasing the Valency of Interfacial Assemblies: Dendrimers, Oligomers, and Polymers 53

2.4.2 Heterotropic Interactions 58

2.4.3 Kinetics and Dynamics 63

2.5 Conclusions 68

Acknowledgments 68

References 68

3 Design Principles for Super Selectivity using Multivalent Interactions 75
Tine Curk, Jure Dobnikar, and Daan Frenkel

3.1 Introduction 75

3.1.1 Background: Ultra -sensitive Response 75

3.2 Super selectivity: An emergent property of multivalency 78

3.3 Multivalent Polymer Adsorption 84

3.4 Which Systems are Super Selective? 86

3.4.1 Rigid Geometry Interactions 86

3.4.2 Disordered Multivalency 87

3.5 Design Principles for Super -Selective Targeting 90

3.6 Summary: It is interesting, but is it useful? 93

Appendix 3.A: What Is Effective Molarity? 95

Acknowledgements 98

References 98

4 Multivalency in Biosystems 103
Jens Dernedde

4.1 Introduction 103

4.2 Cell–Cell Adhesion 104

4.2.1 Homotypic Interactions, Cadherins Keep Cells Together 105

4.2.2 Selectins, Heterotypic Cell Adhesion to Fight Infections 106

4.2.3 Bacterial Adhesion by FimH 108

4.3 Phase Transition, Multivalent Intracellular Assemblies 109

4.4 Multivalency in the Fluid Phase, Pathogen Opsonization 111

4.5 Conclusion 113

Acknowledgment 113

References 114

Part II Multivalent Systems in Chemistry 121

5 Multivalency in Cyclodextrin/Polymer Systems 123
Akihito Hashidzume and Akira Harada

5.1 Introduction 123

5.2 General Perspectives of Multivalency in Cyclodextrin/Polymer Systems 125

5.3 Typical Examples of Multivalency in Cyclodextrin/Polymer Systems 126

5.3.1 Formation of Polymer Aggregates from Cyclodextrin -Polymers and Guest -Polymers 126

5.3.2 Selectivity of Interaction Enhanced by Multivalency 127

5.3.3 Self -Healable Hydrogels Based on Multivalency 134

5.4 Summary and Outlook 136

Acknowledgments 136

References 138

6 Cucurbit[n-uril -Mediated Multiple Interactions 143
Zehuan Huang and Xi Zhang

6.1 Introduction to Cucurbit[n-uril Chemistry 143

6.2 Heteroternary Complexes 143

6.3 Homoternary Complexes 146

6.4 Conclusions 150

References 150

7 Multivalency as a Design Criterion in Catalyst Development 153
Paolo Scrimin, Maria A. Cardona, Carlos M. Leon Prieto, and Leonard J. Prins

7.1 Introduction 153

7.2 Formation of Enzyme -Like Catalytic Pockets 154

7.3 Cooperativity Between Functional Groups 157

7.4 Mechanistic Effects 161

7.5 The Dendritic Effect in Multivalent Nanozymes 164

7.5.1 Peptide -Based Dendrimers for the Cleavage of Phosphodiesters 166

7.5.2 Catalytic 3D SAMs on Au NPs 168

7.6 Multivalent Catalysts and Multivalent Substrates 170

7.7 Conclusions 172

Acknowledgements 174

References 174

8 Multivalent Molecular Recognition on the Surface of Bilayer Vesicles 177
Jens Voskuhl, Ulrike Kauscher, and Bart Jan Ravoo

8.1 Introduction 177

8.2 Molecular Recognition of Vesicles 179

8.2.1 Metal Coordination 180

8.2.2 Light Responsive Interactions 184

8.2.3 Hydrogen Bonding and Electrostatic Interactions 185

8.3 Biomimetic Vesicles 188

8.3.1 Vesicles as Multivalent Platforms 188

8.3.2 Membrane Fusion 193

8.4 Vesicle -based Supramolecular Materials 196

8.4.1 Hydrogels 196

8.4.2 Immobilization of Vesicles 198

8.4.3 Nanoparticles and Nanocontainers 198

8.5 Conclusion 201

Acknowledgment 201

References 201

Part III Multivalent Systems in Biology 205

9 Blocking Pathogens by Multivalent Inhibitors 207
Sumati Bhatia, Benjamin Ziem, and Rainer Haag

9.1 Introduction 207

9.2 Design of Multivalent Ligand Architectures 209

9.3 Multivalent Carbohydrate Ligands 212

9.4 Scaffold Architecture 215

9.4.1 “Soft” Linear and Dendritic 215

9.4.2 Rigid Core Multivalent Nanoparticles 218

9.5 2 D Platforms 220

9.6 Nano -and Microgels for Pathogen Inhibition 222

9.7 Conclusion 223

Acknowledgments 224

References 224

10 Multivalent Protein Recognition Using Synthetic Receptors 229
Akash Gupta, Moumita Ray, and Vincent M. Rotello

10.1 Introduction 229

10.2 Structural Properties of Protein Surfaces 229

10.2.1 Protein–Protein Interfacial Areas 229

10.2.2 Chemical Nature of the Protein–Protein Interface 230

10.2.3 “Hot Spots” 230

10.2.4 O -Ring Structure 232

10.3 Synthetic Receptors for Protein Surface Recognition 232

10.3.1 Porphyrin Scaffolds for Protein Surface Recognition 232

10.3.2 Protein Surface Recognition Using Molecular Tweezers 238

10.3.3 Calixarene Scaffolds for Protein Surface Recognition 240

10.3.4 Recognition of Protein Surfaces Using Nanoparticles 243 Nanoparticles as Protein Mimics 244 Regulating the Structure and Function of Proteins Using Nanoparticles 246 Nanoparticle -based Protein Sensors 250

10.4 Future Perspective and Challenges 254

Acknowledgment 257

References 257

11 Multivalent Calixarenes for the Targeting of Biomacromolecules 263
Francesco Sansone and Alessandro Casnati

11.1 Introduction 263

11.2 Binding to Proteins and Enzymes 266

11.3 Recognition of Carbohydrate Binding Proteins (Lectins) 273

11.4 Binding Polyphosphates, Oligonucleotides and Nucleic Acids 279

11.5 Conclusions 284

Acknowledgements 285

References 285

12 Cucurbit[n-uril Assemblies for Biomolecular Applications 291
Emanuela Cavatorta, Luc Brunsveld, Jurriaan Huskens, and Pascal Jonkheijm

12.1 Introduction 291

12.2 Molecular Recognition Properties of CB[n- 293

12.2.1 Interactions with the Carbonyl Portals of CB[n- 293

12.2.2 Release of High Energy Water Molecules from the CB[n- Cavity 295

12.2.3 Enthalpy -driven Hydrophobic Effect for CB[n- 295

12.2.4 Enthalpy -driven Hydrophobic Effect for CB[8- Heteroternary Complexes 297

12.3 Control Over the Binding Affinity with CB[n- 299

12.4 CB[n- Recognition of Amino Acids, Peptides, and Proteins 301

12.5 CB[n- for Bioanalytical and Biomedical Applications 305

12.5.1 CB[n- -mediated Assembly of Bioactive Polymers and Hydrogels 305

12.5.2 CB[n- -mediated Assembly of Bioactive Nanoparticles 307

12.5.3 CB[n- -mediated Assembly on Bioactive Surfaces 313

12.6 Conclusions and Outlook 317

Acknowledgment 319

References 319

13 Multivalent Lectin–Glycan Interactions in the Immune System 325
Joao T. Monteiro and Bernd Lepenies

13.1 Introduction 325

13.2 Targeting Innate Immunity to Shape Adaptive Immunity 327

13.3 C -type Lectin Receptors 328

13.3.1 Multivalent Glycoconjugates Targeting DC -SIGN 331

13.3.2 Multivalent Glycoconjugates Targeting Other CLRs 331

13.4 Galectins 332

13.5 Siglecs 334

13.6 Conclusions 335

Acknowledgment 335

References 335

14 Blocking Disease Linked Lectins with Multivalent Carbohydrates 345
Marjon Stel and Roland J. Pieters

14.1 Introduction 345

14.2 Haemagglutinin 347

14.3 LecA 349

14.4 LecB 354

14.5 Galectins 358

14.6 Concanavalin A 362

14.7 Cholera Toxin 366

14.8 Propeller Lectins 367

14.9 Conclusion 371

Acknowledgements 371

References 371


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Author Information

Jurriaan Huskens, PhD (1968) is full professor “Molecular Nanofabrication” at the University of Twente. He studied chemical engineering at the Eindhoven University of Technology, and obtained his PhD (1994) at the Delft University of Technology with Herman van Bekkum. He received the Unilever Research Award 1990, a Marie Curie fellowship (1997), and the Gold Medal 2007 of the Royal Netherlands Chemical Society. Present research interests encompass: supramolecular chemistry at interfaces, supramolecular materials, multivalency, nanofabrication, and solar fuels. 

Leonard Prins, PhD is a professor in Organic Chemistry at the University of Padova, Italy. He earned a doctorate from the University of Twente (Netherlands) in 2001 and worked as postdoctoral fellow at Caltech (Pasadena, USA) and the University of Padova (Italy).  He has been awarded the H.J.-Backer price 2001 by the Dutch Royal Chemical Society (KNCV), the 2008 European Young Chemist Award (silver) by the European Association for Chemical and Molecular Sciences (EuCheMs) and the 2008 'Ciamician' medal by the Organic Chemistry Division of the Italian Chemical Society (SCI). His current research interests include the study of network reactivity in complex chemical systems and the origin of cooperativity in multivalent catalysts.

Rainer Haag, PhD joined the Freie Universität Berlin as full Professor of Organic and Macromolecular Chemistry in 2004. He studied at the Technische Universität Darmstadt and the University of Göttingen, and obtained his PhD with A. de Meijere at the latter institution in 1995. Prof. Haag's main research interests are the mimicry of biological systems by functional dendritic polymers, with a particular focus on bioactive surfaces, multivalent nanosystems for the inhibition of pathogens, and stimuli-responsive nanocarriers for targeted drug delivery. Currently he serves on the Editorial Board of the Angewandte Chemistry and is the spokesperson of the collaborative research center 765 on “multivalency."

Bart Jan Ravoo, PhD (1970) is full professor at the University of Münster, Germany, where he is in charge of the "Synthesis of Nanoscale Systems" group. Since 2016 he is co-director of the Center for Soft Nanoscience (SoN). Bart Jan Ravoo obtained his graduate and postgraduate degrees from the University of Groningen, The Netherlands.  He moved to University College Dublin, Ireland, in 1999 and obtained a Newman Scholarship in Organic Chemistry for a period of three years. In 2002 he was appointed as assistant professor at the University of Twente, The Netherlands. His main research interest are soft materials made by self-assembly, functional nanoparticles, and self-assembled monolayers.

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