Preface ix 1 What Could Bring Theory to Modern Bioinorganics: A Conversation? 1 Gerard Roelfes and Jean-Didier Maréchal 2 Computational Prediction and Modeling of Metal-binding Sites in Proteins 9 José-Emilio Sánchez-Aparicio, Giuseppe Sciortino, and Jean-Didier Maréchal 2.1 Introduction 9 2.2 Experimental Tools 10 2.3 Computational Tools 10 2.3.1 Pattern Recognition Algorithms 11 2.3.2 The Backbone Preorganization Hypothesis 14 2.

3.3 Protein-Ligand Dockings 17 2.3.4 GaudiMM Platform 19 2.3.5 Quantum Mechanical and Hybrid Approaches 21 2.3.6 Molecular Dynamics, Integrative or Multiscale Approaches 22 2.

4 Conclusions 25 References 25 3 Quantum-mechanics Approaches in Bioinorganic Chemistry: Targeting the Oxidation State 33 Marcel Swart 3.1 Introduction 33 3.2 Experimental Observations 35 3.3 Quantum-chemistry Approaches 37 3.3.1 Chemical Bonding Analyses 38 3.3.2 Oxidation States from Wavefunctions or Densities 41 3.

4 Classical Examples 43 3.5 Intriguing Examples 46 3.6 Summary and Outlook 48 Acknowledgments 49 References 49 4 Computation and Spectroscopy 57 Eugenio Garribba 4.1 Introduction 57 4.2 Software, Computational Techniques, and Statistical Indicators 58 4.3 Electron Paramagnetic Resonance 61 4.4 Electron Spin Echo Envelope Modulation and Electron-nuclear Double Resonance 67 4.5 Nuclear Magnetic Resonance 69 4.

6 Electron Absorption Spectroscopy 77 4.7 Circular Dichroism and Magnetic Circular Dichroism 81 4.8 Vibrational Spectroscopy 83 4.9 Mossbauer Spectroscopy 84 4.10 Conclusions 88 References 89 5 Multiscale Computational Modeling for the Discovery and Characterization of New Metalloenzyme-catalyzed Reactions 99 Ferran Feixas and Marc Garcia-Borràs 5.1 Importance of Metalloenzymes 99 5.2 Multi-scale Computational Microscope for Modeling Metalloenzymatic Reaction Mechanisms 100 5.2.

1 Classical Molecular Dynamics Simulations 102 5.2.2 Truncated Active Site Models at the Quantum Mechanics Level 103 5.2.3 Hybrid Quantum Mechanics/Molecular Mechanics 103 5.3 Practical Considerations for Computational Modeling of Metalloenzymes 104 5.3.1 Selecting the Starting Structure 104 5.

3.2 Initial Exploration of Conformational Dynamics 105 5.3.3 Placement of Substrate or Reaction Intermediate 106 5.4 The Mechanistic Versatility of P450s Through the Lens of a Computational Microscope: Practical Examples 107 5.4.1 Practical Example: Anti-Markovnikov Alkene Oxidations Catalyzed by P450s 108 5.4.

2 Molecular Dynamics Simulations for Modeling the Protein Environment 112 5.4.3 Insightful Revelations from QM/MM Calculations 114 5.4.4 The Role of Local Electric Fields in Enzymatic Reactions 116 5.5 Conclusions 117 Acknowledgments 118 References 119 6 Force Fields and Metals 123 José-Emilio Sánchez-Aparicio, Lorena Roldán-Martín, Jean-Didier Maréchal, and Giuseppe Sciortino 6.1 Introduction 123 6.2 Overview on Molecular Mechanics and How to Deal with Metals 124 6.

3 Bonded Model 126 6.3.1 Cu(II) Binding to Polyhistidine Peptides 126 6.3.2 Interaction of Oxaliplatin with Insulin 127 6.3.3 Artificial Metallohydratase 128 6.4 Nonbonded Models 131 6.

4.1 The Dummy Atom 131 6.5 The 12-6(-4) Lennard-Jones Potentials 132 6.6 Conclusions 134 References 135 7 Modeling Thermally Activated Processes 139 Pietro Vidossich and Alessandra Magistrato 7.1 Introduction 139 7.2 Modeling Transitions 140 7.2.1 Theoretical Framework 141 7.

2.2 Collective Variables 142 7.2.3 Biased Methods 144 7.3 Illustrative Studies 147 7.3.1 Metal Coordination 147 7.3.

2 Enzymatic Reactions 150 7.4 Conclusion 153 References 154 8 Metal-induced Folding of Oligopeptides 159 L. Roldán-Martín, L. Rodríguez-Santiago, J. Alí-Torres, J. D. Maréchal, and M. Sodupe 8.

1 Introduction 159 8.2 Metal-Ligand Interactions with Short Peptides (n = 2-8) 160 8.2.1 Gly n and Ala n Metal Complexes 160 8.2.2 Metal-Peptide Complexes Involving Residues Other than Gly and Ala 163 8.3 Metal-oligopeptides (n >8) 165 8.3.

1 Construction of Three-dimensional Models. Application to Cu 2+ -Aβ 1-16 166 8.3.2 Impact of Cu 2+ and Al 3+ Binding on the Aβ 1-42 Conformational Landscape 169 8.4 Conclusions 172 References 172 9 Computational Studies of Metallodrugs 179 James A. Platts and Matthew Turner 9.1 Introduction 179 9.2 QM Studies of Metallodrugs and Their Solvation 179 9.

3 QM Studies of Metallodrug-Biomolecule Interactions 181 9.4 QM/MM Modeling of Drug-Biomolecule Interactions 184 9.5 Classical MM Description of Drugs and Their Interactions 186 9.6 Docking and QSAR Studies 190 9.7 Conclusion 191 References 192 10 Computational Design of Artificial Metalloenzymes 195 Laura Tiessler-Sala, Maria Fatima Lucas, and Emanuele Monza 10.1 Introduction 195 10.2 Typical Computational Pipeline 196 10.3 Critical Aspects and Frontiers of ArM Design 198 10.

3.1 Challenges in Modeling Metallic Centers 198 10.3.2 Unnatural Amino Acids Can Unlock New Reactivity 200 10.3.3 Beyond TS Stabilization 202 10.3.4 The New Era: De Novo Protein Design with DL 204 10.

4 Concluding Remarks 205 References 206 11 How Computational Chemistry Can Contribute to the Understanding of the Effects of Metal Ions in Biological Systems: Aluminum as a Case Study 213 J.I. Mujika and X. Lopez 11.1 Introduction 213 11.2 Aluminum 215 11.2.1 Aluminum Speciation in Water 216 11.

2.2 Mapping Aluminum Speciation with Biological Building Molecules 217 11.3 The Pro-oxidant Activity of Aluminum 217 11.4 Unveiling the Al(III) − Aβ Complex 223 11.4.1 Step 1: Most Favorable First Coordination Spheres of Aluminum 225 11.4.2 Step 2: The Building of Preliminary Al.

AβComplexes 227 11.4.3 Step 3: Refinement of the Al.AβComplexes 228 11.5 In Silico Design of Novel Aluminum Chelators 231 11.6 Concluding Remarks 237 References 237 Index 239.