Molecular Structures and Structural Dynamics of Prion Proteins and Prions: Mechanism Underlying the Resistance to Prion Diseases (Focus on Structural Biology Book 9)

This monograph is the first easy-to-read-and-understand book on prion proteins' molecular dynamics (MD) simulations and on prions' molecular modelling (MM) constructions. It enables researchers to see what is crucial to the conformational change from normal cellular prion protein (PrP C ) to diseased infectious prions (PrP Sc ), using MD and MM techniques. As we all know, prion diseases, caused by the body's own proteins, are invariably fatal and highly infectious neurodegenerative diseases effecting humans and almost all animals for a major public health concern. Prion contains no nucleic acids and it is a misshapen or conformation-changed protein that acts like an infectious agent; thus prion diseases are called “protein structural conformational” diseases. PrP C is predominant in α-helices but PrP Sc are rich in β-sheets in the form as amyloid fibrils; so very amenable to be studied by MD techniques. Through MD, studies on the protein structures and the structural conversion are very important for revealing secrets of prion diseases and for structure-based drug design or discovery. Rabbits, dogs, horses and buffaloes are reported to be the few low susceptibility species to prion diseases; this book's MD studies on these species are clearly helpful to understand the mechanism underlying the resistance to prion diseases. PrP(1-120) usually has no clear molecular structures; this book also studies this unstructured region through MD and especially MM techniques from the global optimization point of view. This book is ideal for practitioners in computing of biophysics, biochemistry, biomedicine, bioinformatics, cheminformatics, materials science and engineering, applied mathematics and theoretical physics, information technology, operations research, biostatistics, etc. As an accessible introduction to these fields, this book is also ideal as a teaching material for students. Preface 8 Contents 10 About the Author 16 Acronyms 18 1 Basic Knowledge 21 1.1 Protein Structures and Functions 21 1.1.1 Prion Proteins and Prions 23 1.2 Protein Structural Dynamics and Molecular Dynamics 24 1.3 Molecular Modeling 25 1.3.1 Algorithms to Minimize the Total Potential Energy and the Lennard-Jones Potential Energy 26 Part I Molecular Dynamics of Prion Proteins 34 Introduction 34 2 The Homology Structure and Dynamics 36 2.1 Molecular Modeling 36 2.2 The Homology Rabbit Prion Protein at 500K 37 2.3 Molecular Dynamics Methods at 300 and 450K 37 2.4 Results at 450K and Discussion 38 2.5 Concluding Remarks 41 3 The NMR Structure and Dynamics of the Wild-Type and Mutants 43 3.1 Overview 43 3.2 Materials and Methods 44 3.3 Results and Discussion 44 3.4 A Concluding Remark 46 4 Compared with the NMR Structure and Dynamics of Humans and Mice 47 4.1 Overview 47 4.2 Materials and Methods for 300 and 450K 47 4.3 Results and Discussion for 300 and 450K 48 4.4 Concluding Remarks for the 300 and 450K 54 4.5 Molecular Dynamics at 350K 54 5 Compared with the NMR Structure and Dynamics of Dogs and Horses 57 5.1 Rabbits Compared with Dogs 57 5.1.1 Overview 57 5.1.2 Materials and Methods at 300 and 450K 58 5.1.3 Results and Discussions for 300 and 450K 59 5.1.4 Concluding Remarks 64 5.2 Rabbits Compared with Horses 64 5.2.1 Overview 64 5.2.2 Materials and Methods for 350K 65 5.2.3 Results and Discussions for 350K 66 5.2.4 Concluding Remarks 70 5.2.4.1 Salt Bridges: A Clue of Rabbits Resisting Prion Diseases 70 5.3 Rabbits Compared with Horses and Dogs at 350K 72 5.3.1 Materials and Methods 73 5.3.2 Results and Discussion 73 5.3.3 A Concluding Remark 75 5.4 Alignment Analyses 76 5.5 Conclusion 78 6 Compared with a Homology Structure and Dynamics of Buffaloes 79 6.1 Introduction 79 6.2 Materials and Methods 81 6.2.1 Homology Structure for BufPrPC(124–227) 81 6.2.2 Molecular Dynamics (MD) Techniques 82 6.3 Results and Discussion 83 6.3.1 BufPrP Homology Structure Has 5 Hydrogen Bonds at Asn143 83 6.3.2 BufPrP Is Stable Under Neutral or Low pH Environments at Room Temperature 83 6.3.3 Some Special Contributions to the Stable BufPrP 93 6.4 Compared with Rabbits 96 6.5 Concluding Remarks 97 7 Compared with the NMR Structure and Dynamics of Elks 99 7.1 Results of Molecular Dynamics at 300K 99 7.2 Results of Molecular Dynamics at 450K 99 7.3 A Concluding Remark Compared with Rabbit PrP 103 8 Compared with the X-Ray Structure and Dynamics of Rabbits 105 8.1 Introduction 105 8.2 A Detailed Review on Rabbit PrP 107 8.3 Materials and Methods for MD of RaPrP X-Ray Structure 115 8.4 Results and Discussions 116 8.4.1 450K 116 8.4.2 At 300K (the Room Temperature) 119 8.4.3 At 350K 120 8.4.4 Hydrogen Bonds 121 8.5 Conclusion 121 8.6 Review on the Salt Bridge Asp177-Arg163 (O-N) of RaPrP 123 8.6.1 Introduction 124 8.6.2 Materials and Methods 125 8.6.3 Results and Discussion 126 8.6.3.1 Confirmation from the X-Ray Structure 3O79.pdb File 126 8.6.3.2 Confirmation from the MD of X-Ray 3O79.pdb Structure at 300K Room Temperature 126 8.6.3.3 Confirmation from the MD of the NMR 2FJ3.pdb Structure at 300K Room Temperature 132 8.6.3.4 Confirmation from the MD of the NMR 2FJ3.pdb Structure at 350 and 450K 134 8.6.3.5 Confirmation from the MD of the Homology Structure of RaPrPC at 500K 134 8.6.4 Conclusion 135 9 Surface Electrostatic Charge Distributions 136 9.1 Wild-Type RaPrP Compared with its Mutants, Humans, Mice, Horses and Dogs 136 9.2 From the MD Results of NMR RaPrP and Mutants 140 9.2.1 Introduction 141 9.2.2 Materials and Methods 143 9.2.2.1 Discussion on the MD Methods 144 9.2.2.2 Discussion on Dielectrique Constant and Free Energy 145 9.2.2.3 About Dielectric Constant 146 9.2.3 Results and Discussion 146 9.2.4 Conclusions 151 9.3 Other Clues 152 9.3.1 Weak and Strong Copper Bindings 152 9.3.2 π-π Stackings and π-Cations in All PrPC Structures 153 10 The Hydrophobic Region PrP(109–136) 160 10.1 Introduction 160 10.2 Structural Studies on the PrP(119–131) GAVVGGLGGYMLG 162 10.3 Concluding Remarks on PrP(109–136) 169 10.4 Prion AGAAAAGA Amyloid Fibril Structures 170 10.5 Recent Research Advances in the Mammalian PrP Glycine-xxx-Glycine Motif 172 10.6 A Survey on the (Central) Hydrophobic Region of PrP 173 10.6.1 Introduction 173 10.6.2 A Detailed Review on PrP Central Hydrophobic Region 174 Part II Molecular Modeling of Prions 184 Introduction 184 11 The Hybrid Method of Steepest Descent: Conjugate Gradient with Simulated Annealing 187 11.1 Steepest Descent Local Search Method 187 11.2 Conjugate Gradient Local Search Method 187 11.2.1 Overview 188 11.2.2 The Proof for Convergence 189 11.2.3 Concluding Remarks 197 11.3 Simulated Annealing Global Optimization Search Algorithm 197 11.4 The Application of Hybrid SDCG-SA-SDCG Method 198 11.4.1 Overview 198 11.4.2 Materials and Methods 199 11.4.3 Results and Discussion 201 11.4.4 Concluding Remarks 206 11.5 Implementing Simulated Annealing in Global Optimization Computations 206 11.5.1 Overview 208 11.5.2 Initial Feasible Solution Producing Procedure 209 11.5.3 Initial Temperature Selecting Procedure 210 11.5.4 Neighborhood Solution Searching Procedure 211 11.5.5 Efficient Calculation of Cost Difference 214 11.5.6 Acceptance Function 214 11.5.7 Cooling Scheduling of Temperature 215 11.5.8 Stopping Criterion of Inner Loops 216 11.5.9 Stopping Criterion of Outer Loops 217 12 Hybrid Method of Discrete Gradient with Simulated Annealing or Genetic Algorithm 218 12.1 Overview 218 12.2 The Optimization Model Building 220 12.3 Model Solving/Optimization 229 12.4 Results and Discussion 230 12.5 Concluding Remarks 233 13 A Novel Canonical Dual Global Optimization Computational Approach 234 13.1 Overview 234 13.2 The Canonical Dual Global Optimization Approach 236 13.3 Prion AGAAAAGA Amyloid Fibril Model Building & Solving 239 13.4 Concluding Remarks 248 13.5 Other Models 248 13.5.1 Overview 249 13.5.2 Applications to a Lennard-Jones Potential Optimization Problem 251 13.5.2.1 3NVF 251 13.5.2.2 3NVG 256 13.5.2.3 3NVH 259 13.5.2.4 Refined 3nvf-Models 1–3, 3nvg-Models 1–3, 3nvh-Models 1–2 262 13.5.3 Concluding Remarks 264 13.5.4 3MD4/5 Models 264 13.5.5 3NVE Models 272 14 The Hybrid Method of Evolutionary Computations with Simulated Annealing 278 14.1 Overview 278 14.2 Prion AGAAAAGA Amyloid Fibril Models' Molecular Modeling and Optimizing 282 14.3 Concluding Remarks 284 14.4 Another Application 285 14.4.1 Introduction 285 14.4.2 Molecular Structures of AGAAAAGA Amyloid Fibrils 286 14.4.2.1 Review on Materials and Methods, and Results of MM Models 287 14.4.2.2 New Material and Method, and New MM-Models 288 14.4.2.3 A New Thinking About Protein 3D-Structure Constructions 293 14.4.3 Conclusions 295 15 Simulated Annealing Refined Replica Exchange Global Search Algorithm 297 16 LBFGS Quasi-Newtonian Methods for Molecular Modeling Prion AGAAAAGA Amyloid Fibrils 304 16.1 Introduction 304 16.2 Methods 307 16.3 Results and Discussion 314 16.3.1 Material for the Molecular Modeling 314 16.3.2 New Molecular Modeling Homology Model 316 16.4 Conclusion 320 17 Particle Swarm Global Optimization Search Algorithm 321 17.1 A Brief Introduction to Particle-Swarm-Type Algorithms 321 18 A Summary of the Research Works on AGAAAAGA 323 References 328 Index 362 This Monograph Is The First Easy-to-read-and-understand Book On Prion Proteins' Molecular Dynamics (md) Simulations And On Prions' Molecular Modelling (mm) Constructions. It Enables Researchers To See What Is Crucial To The Conformational Change From Normal Cellular Prion Protein (prpc) To Diseased Infectious Prions (prpsc), Using Md And Mm Techniques. As We All Know, Prion Diseases, Caused By The Body's Own Proteins, Are Invariably Fatal And Highly Infectious Neurodegenerative Diseases Effecting Humans And Almost All Animals For A Major Public Health Concern. Prion Contains No Nucleic Acids And It Is A Misshapen Or Conformation-changed Protein That Acts Like An Infectious Agent; Thus Prion Diseases Are Called “protein Structural Conformational” Diseases. Prpc Is Predominant In α-helices But Prpsc Are Rich In β-sheets In The Form As Amyloid Fibrils; So Very Amenable To Be Studied By Md Techniques. Through Md, Studies On The Protein Structures And The Structural Conversion Are Very Important For Revealing Secrets Of Prion Diseases And For Structure-based Drug Design Or Discovery. Rabbits, Dogs, Horses And Buffaloes Are Reported To Be The Few Low Susceptibility Species To Prion Diseases; This Book's Md Studies On These Species Are Clearly Helpful To Understand The Mechanism Underlying The Resistance To Prion Diseases. Prp(1-120) Usually Has No Clear Molecular Structures; This Book Also Studies This Unstructured Region Through Md And Especially Mm Techniques From The Global Optimization Point Of View. This Book Is Ideal For Practitioners In Computing Of Biophysics, Biochemistry, Biomedicine, Bioinformatics, Cheminformatics, Materials Science And Engineering, Applied Mathematics And Theoretical Physics, Information Technology, Operations Research, Biostatistics, Etc. As An Accessible Introduction To These Fields, This Book Is Also Ideal As A Teaching Material For Students. Basic Knowledge -- The Homology Structure And Dynamics -- The Nmr Structure And Dynamics Of The Wild-type And Mutants -- Compared With The Nmr Structure And Dynamics Of Humans And Mice -- Compared With The Nmr Structure And Dynamics Of Dogs And Horses -- Compared With A Homology Structure And Dynamics Of Buffaloes -- Compared With Nmr Structure And Dynamics Of Elks -- Compared With The X-ray Structure And Dynamics Of Rabbits -- Surface Electrostatic Charge Distributions -- The Hydrophobic Region Prp(109–136) -- The Hybrid Method Of Steepest Descent - Conjugate Gradient With Simulated Annealing -- Hybrid Method Of Discrete Gradient With Simulated Annealing Or Genetic Algorithm -- A Novel Canonical Dual Global Optimization Computational Approach -- The Hybrid Method Of Evolutionary Computations With Simulated Annealing -- Simulated Annealing Refined Replica Exchange Global Search Algorithm -- Lbfgs Quasi-newtonian Methods For Mm Prion Agaaaaga Amyloid Fibrils -- Particle Swarm Global Optimization Search Algorithm -- A Summary Of The Research Works On Agaaaaga. By Jiapu Zhang. This monograph is the first easy-to-read-and-understand book on prion proteins' molecular dynamics (MD) simulations and on prions' molecular modelling (MM) constructions.℗l It enables researchers to see what is crucial to the conformational change from normal cellular prion protein (PrPC) to diseased infectious prions (PrPSc), using MD and MM techniques. As we all know, prion diseases, caused by the body's own proteins, are invariably fatal and highly infectious neurodegenerative diseases effecting humans and almost all animals for a major public health concern. Prion contains no nucleic acids and it is a misshapen or conformation-changed protein that acts like an infectious agent; thus prion diseases are called ĺlprotein structural conformationalĺl diseases. PrPC is predominant in lł-helices but PrPSc are rich in lø-sheets in the form as amyloid fibrils; so very amenable to be studied by MD techniques. Through MD, studies on the protein structures and the structural conversion are very important for revealing secrets of prion diseases and for structure-based drug design or discovery. Rabbits, dogs, horses and buffaloes are reported to be the few low susceptibility species to prion diseases; this book's MD studies on these species are clearly helpful to understand the mechanism underlying the resistance to prion diseases. PrP(1-120) usually has no clear molecular structures; this book also studies this unstructured region through MD and especially MM techniques from the global optimization point of view. This book is ideal for practitioners in computing of biophysics, biochemistry, biomedicine, bioinformatics, cheminformatics, materials science and engineering, applied mathematics and theoretical physics, information technology, operations research, biostatistics, etc. As an accessible introduction to these fields, this book is also ideal as a teaching material for students Front Matter....Pages i-xix Basic Knowledge....Pages 1-13 Front Matter....Pages 15-16 The Homology Structure and Dynamics....Pages 17-23 The NMR Structure and Dynamics of the Wild-Type and Mutants....Pages 25-28 Compared with the NMR Structure and Dynamics of Humans and Mice....Pages 29-38 Compared with the NMR Structure and Dynamics of Dogs and Horses....Pages 39-60 Compared with a Homology Structure and Dynamics of Buffaloes....Pages 61-80 Compared with the NMR Structure and Dynamics of Elks....Pages 81-86 Compared with the X-Ray Structure and Dynamics of Rabbits....Pages 87-117 Surface Electrostatic Charge Distributions....Pages 119-142 The Hydrophobic Region PrP(109–136)....Pages 143-166 Front Matter....Pages 167-169 The Hybrid Method of Steepest Descent: Conjugate Gradient with Simulated Annealing....Pages 171-201 Hybrid Method of Discrete Gradient with Simulated Annealing or Genetic Algorithm....Pages 203-218 A Novel Canonical Dual Global Optimization Computational Approach....Pages 219-262 The Hybrid Method of Evolutionary Computations with Simulated Annealing....Pages 263-281 Simulated Annealing Refined Replica Exchange Global Search Algorithm....Pages 283-289 LBFGS Quasi-Newtonian Methods for Molecular Modeling Prion AGAAAAGA Amyloid Fibrils....Pages 291-307 Particle Swarm Global Optimization Search Algorithm....Pages 309-310 A Summary of the Research Works on AGAAAAGA....Pages 311-315 Back Matter....Pages 317-355