Molecular Structures And Structural Dynamics Of Prion Proteins And Prions
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Molecular Structures and Structural Dynamics of Prion Proteins and Prions
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.
Molecular Dynamics Analyses of Prion Protein Structures
Unlike bacteria and viruses, which are based on DNA and RNA, prions are unique as disease-causing agents since they are misfolded proteins. Prion diseases are called "protein structural conformational” diseases. This monograph is the book on molecular dynamics (MD) simulations nearly for all the known normal prion protein (PrPC) PDB entries in the Protein Data Bank (PDB) and associations. Pig is a species that is largely resistant to prions, and chicken, turtles, frogs are species resisting prion infection too; firstly, this book will address all PrP strong immunity species (such as rabbits, dogs, horses, water buffaloes, pigs, chicken, turtles, frogs), compared with high susceptibility species. Other PrP models and doppel models are also MD studied in this book. Secondly, all the mutants of mouse PrP and human PrP are well studied by this book. Mouse mutations in the β2-α2 loop and the C-terminal will bring clear structures with highly and clearly ordered loop structures. Human mutations will cause prion diseases such as Creutzfeldt-Jakob diseases (CJDs), Gerstmann-Sträussler-Scheinker (GSS) syndrome, fatal familial insomnia (FFI), etc. Deep MD analyses of mouse and human mutants are done in this book. Thirdly, PrP binding with antibodies/compounds etc. is well MD studied in this book. The informatics of potential antiprion drugs known will be revealed. Lastly, cross-β structure PrP peptides are well studied. This book is ideal for practical computing staff in the fields of computational physics, computational biology, computational chemistry, biomedicine, bioinformatics, cheminformatics, materials, 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.
Optimization-based Molecular Dynamics Studies of SARS-CoV-2 Molecular Structures
COVID-19 has brought us extensive research databases in the fields of biophysics, biology, and bioinformatics. To extract valuable structural bioinformatic information of SARS-CoV-2 structural and nonstructural proteins, it is necessary to work with large-scale datasets of molecular dynamics (MD) trajectories that need to be optimized. This monograph serves as a comprehensive guide to optimization-based MD studies of the molecular structures of SARS-CoV-2 proteins and RNA. The book begins by performing local optimization, taking into account the three-body movement and optimizing the noncovalent bonds of each molecular structure. The optimized structures reach a transition state that offers the best stability and lowest energy. The optimization process utilizes a hybrid strategy that combines mathematical optimization with various local search algorithms. This approach significantly reduces data volume while eliminating irrelevant bioinformatics data. To gain a thorough understanding of molecular stability and the mechanism of action, it is essential to consider not only static NMR, X-ray, or cryo-EM structures but also dynamic information obtained through MD or Quantum Mechanics/Molecular Mechanics (QM/MM) simulations. These simulations capture the internal motions and dynamic processes of molecules. Furthermore, for each protein, the structural bioinformatics obtained from the optimized structure is validated by analyzing large-scale MD trajectory databases, which are openly and freely available online. The analysis includes key structural bioinformatics aspects such as salt bridge electrostatic interactions, hydrogen bonds, van der Waals interactions, and hydrophobic interactions specific to each SARS-CoV-2 molecular structure. The book also delves into discussions on drugs, vaccines, and the origins of the virus. Additionally, pandemic mathematical models, including those incorporating time delays, are explored. This book is particularly valuable for professionals working in practical computing roles within computational biochemistry, computational biophysics, optimization and molecular dynamics, structural bioinformatics, biological mathematics, and related fields. It serves as an accessible introduction to these disciplines and is also an excellent teaching resource for students.