Unlike bacteria and viruses, which are based on DNA and RNA, prions are unique as disease-causing agents since they are misfolded proteins. Prions propagate by deforming harmless, correctly folded proteins into copies of themselves. The misfolding is irreversible. Prions attack the nervous system of the organism, causing an incurable, fatal deterioration of the brain and nervous system until death occurs. Some examples of these diseases are mad cow disease in cattle, chronic wasting disease in deer and elk, and Creutzfeldt-Jakob disease in humans.
Not every species is affected by prion disease. Rabbits, water buffalo, horses, and dogs are resistant to prion diseases. The research question arises: What is different about the protein in a resistant species (especially the rabbit, which seems to be the most resistant) that allows it to retain its folding? This is the research question addressed in this book. The original research reported in this volume is based on molecular modeling since the usual experimental tools for structure elucidation at the molecular level, X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, are often unsuitable for studying proteins. The computational simulation of the interactions within and among proteins is used to interpret the stability of conformations as they fold and as they pack in a cluster of proteins.
After an introductory chapter in which the author describes the proteins in question and a quick overview of molecular dynamics and molecular mechanics, this book is organized into two parts. The first part is a set of nine chapters in which the author presents primarily the results of his research using the molecular dynamics of segments of the proteins of comparable species in order to explain why rabbits resist prion infection while other susceptible species do not. The second part consists of eight chapters emphasizing the optimization methods used in molecular modeling and molecular dynamics.
In the first part, the molecular dynamics simulations are performed at different computational temperatures and at low, high, and neutral pH levels. Segments of the proteins are selected for detailed analysis. The simulations suggest strongly that the prion-resistant species have stronger intra- and inter-chain interactions in specific segments of the protein chain that stabilize their geometries.
The second part discusses the optimization algorithms used: steepest descent, simulated annealing, genetic algorithm, evolutionary optimization, and combinations of these algorithms. The computational goal is identifying the low-energy conformations and their relative stability with respect to each other, especially the differences between the protein and the prion.
There is much that is very good about this book: the reporting of research results comparing different segments of different species’ proteins, the critical reviews of the existing literature, the extensive bibliography (over 700 publications), and the discussion of the optimization techniques. On the other hand, there are shortcomings: the repetitiveness in introducing each chapter by describing the research problem as if it were brand new; the colored figures that are supposed to show changes in conformation are so small that the scales on the axes cannot be read and they are accompanied by figure descriptions that discuss letter codes, not colors; a section discussing important results presented in a figure in a reference, without reprinting the figure in the book; and the poor copy editing that allowed errors in English grammar and scientific descriptions. It seems that the book was created by taking individual papers and assembling them in sequence with little attention to concision and cohesiveness. Nonetheless, if one can endure and overlook the many flaws in presentation, there is a wealth of information and insight in the results presented and in the methods employed. The research is important. The methods used are innovative. Studying this book is worth the effort.
