This book presents a new approach to the Protein Folding Problem. It starts with a clear description of what the protein folding problem involves. Then, it suggests non-conventional answers to some of the questions posed. In particular, it emphasizes the importance of hydrophilic interactions and hydrophilic forces, rather than the hydrophobic effects, for the stability of the native structure of proteins, as well for the speed of the folding process.
A solution to the protein folding problem has eluded researchers for more than 30 years. The stakes are high. Such a solution will make 40,000 more tertiary structures available for immediate study by translating the DNA sequence information in the sequence databases into three-dimensional protein structures. This translation will be indispensable for the analy sis of results from the Human Genome Project, de novo protein design, and many other areas of biotechnological research. Finally, an in-depth study of the rules of protein folding should provide vital clues to the protein fold ing process. The search for these rules is therefore an important objective for theoretical molecular biology. Both experimental and theoretical ap proaches have been used in the search for a solution, with many promising results but no general solution. In recent years, there has been an exponen tial increase in the power of computers. This has triggered an incredible outburst of theoretical approaches to solving the protein folding problem ranging from molecular dynamics-based studies of proteins in solution to the actual prediction of protein structures from first principles. This volume attempts to present a concise overview of these advances. Adrian Roitberg and Ron Elber describe the locally enhanced sam pling/simulated annealing conformational search algorithm (Chapter 1), which is potentially useful for the rapid conformational search of larger molecular systems.
Protein Physics: A Course of Lectures covers the most general problems of protein structure, folding and function. It describes key experimental facts and introduces concepts and theories, dealing with fibrous, membrane, and water-soluble globular proteins, in both their native and denatured states. The book systematically summarizes and presents the results of several decades of worldwide fundamental research on protein physics, structure, and folding, describing many physical models that help readers make estimates and predictions of physical processes that occur in proteins. New to this revised edition is the inclusion of novel information on amyloid aggregation, natively disordered proteins, protein folding in vivo, protein motors, misfolding, chameleon proteins, advances in protein engineering & design, and advances in the modeling of protein folding. Further, the book provides problems with solutions, many new and updated references, and physical and mathematical appendices. In addition, new figures (including stereo drawings, with a special appendix showing how to use them) are added, making this an ideal resource for graduate and advanced undergraduate students and researchers in academia in the fields of biophysics, physics, biochemistry, biologists, biotechnology, and chemistry. - Fully revised and expanded new edition based on the latest research developments in protein physics - Written by the world's top expert in the field - Deals with fibrous, membrane, and water-soluble globular proteins, in both their native and denatured states - Summarizes, in a systematic form, the results of several decades of worldwide fundamental research on protein physics and their structure and folding - Examines experimental data on protein structure in the post-genome era
Proteins in living systems carry out a great variety of specific functions, each of which depends on the precise three-dimensional structure of a particular protein. Proteins are synthesized in the form of a flexible polypeptide chain that is capable of assuming a vast number of configurations; the transformation of this chain into a specific, relatively rigid three-dimensional structure is called folding--a remarkable process of self-organization. It is known that the amino acid sequences of some proteins have sufficient information to determine their three-dimensional structures. There are other proteins whose folding requires additional information beyond that found in the sequence of the mature protein. This book introduces the central problem of folding mechanisms as well as a number of other closely related issues. This book is neither a textbook nor a treatise. Rather, it is an attempt by several investigators to convey the excitement and challenges of those aspects of the folding problem in which they are actively engaged. The contributors give brief introductions to protein folding from the perspectives of molecular architecture, stability and dynamics, phage genetics, DNA exons, general physiology, and natural selection. They point out emerging new directions, including the suggestion of a class of diseases that result from protein folding defects.
Protein folding remains one of the most exclusive problems of modern biochemistry. Structure analysis has given access to the wealth of the molecular architecture of pro teins. As architecture needs static calculations, protein structure is always related to thermodynamic factors that govern folding and stability of a particular folded protein over the non-organized polypeptide chain. During the past decades a huge amount of thermodynamic data related to protein folding and stability has been accumulated. The data are certainly of importance in dechiffring the protein folding problem. At the same time, the data can guide the con struction of modified and newly synthesized proteins with properties optimized for particular application. The intention of this book is a generation of a data collection which makes the vast amount of present data accessible for multidisciplinary research where chemistry, phy sics, biology, and medicine are involved and also pharmaceutical and food research and technology. It took several years to compile all the data and the author wishes to thank everyone who provided data, ideas or even unpublished results. The author is, in particular, indebted to Prof. Wadso (Lund, Sweden) and IUPAC's Steering Committee on Bio physical Chemistry. Furthermore, support by the Deutsche Forschungsgemeinschafi (INK 16 AI-I) is acknowledged.
The book will discuss classes of proteins and their folding, as well as the involvement of bioinformatics in solving the protein folding problem. In vivo and in vitro folding mechanisms are examined, as well as the failures of in vitro folding, a mechanism helpful in understanding disease caused by misfolding. The role of energy landscapes is also discussed and the computational approaches to these landscapes.
The protein folding problem refers to the correlation of a protein's amino acid sequence and its native three-dimensional structure which is essential for functionality. It still constitutes one of the major challenges in computational biology. One commonly studied model for the protein folding problem is the HP lattice model in which proteins are considered in a fairly abstract representation. However, the HP model proteins exhibit significant parallels to proteins occurring in nature. The solution of the HP lattice mode as a combinatorial optimization problem has been proven to be NP-complete, and there have already been developed various different approaches for efficient algorithms. We study an integer programming formulation of the problem. Starting with an analysis of this model, where we concentrate on symmetry issues, we show how the model can be consolidated by exploiting symmetry properties of the underlying lattice. The main focus lies in the development of specific components of a branch-and-cut framework for the computation of solutions for the HP model by means of integer programming methods. In order to understand the structure of the model, we perform a series of polyhedral studies from which we derive two main classes of cutting planes. Furthermore, we exploit the knowledge of folding principles which are also valid for HP model proteins for the development of related branching strategies. For the solution of a special class of instances, we present an implementation of a genetic algorithm for the generation of primal feasible start solutions. Finally, we document the performance of the methods developed for each of the four topics (model consolidation, primal method, branching strategy and cutting planes) within the branch-and-cut procedure. We present computational results for different types of lattices, where we both consider known benchmark instances from literature and random instances.
This book introduces an approach to protein folding from the point of view of kinetic theory. There is an abundance of data on protein folding, but few proposals are available on the mechanism driving the process. Here, presented for the first time, are suggestions on possible research directions, as developed by the author in collaboration with C C Lin.The first half of this invaluable book contains a concise but relatively complete review of relevant topics in statistical mechanics and kinetic theory. It includes standard topics such as thermodynamics, the Maxwell-Boltzmann distribution, and ensemble theory. Special discussions include the dynamics of phase transitions, and Brownian motion as an illustration of stochastic processes.The second half develops topics in molecular biology and protein structure, with a view to discovering mechanisms underlying protein folding. Attention is focused on the energy flow through the protein in its folded state. A mathematical model, based on the Brownian motion of coupled harmonic oscillators, is worked out in the appendix.
Since the publication of the first edition of mechanisms of protein folding in 1994, significant advances in both the technical and conceptual understanding of protein folding. This new edition has been brought up to date in content, context, and authorship and will make the subject accessibleto a wide range of scientists. The emphasis on experimental approaches has benn maintained from the first edition but this time within the explicit context of simulations and energy surfaces. There is an introductory chapter explaining the 'new' model of protein folding, which takes into account theheterogeneity of the starting state. Advances in interpreting observed kinetic data and the development of technology to observe fast folding reactions and characterize intermediate structures have accompanied this new view and are covered in detail. The term 'molten globule'is often usedincorrectly but here the significance of the term is carefully described at different satges of folding. The concept of the transition state, including the complementary approaches of molecular dynamics and protein engineering, is also discussed in detail. In vitro studies provide the molecularbasis for the thermodynamic and kinetic energy minimization of the in vivo processes of protein folding and two of the potentially rate determining reactions are disulphide bond formation and proline isomerization. It has also become increasingly apparent that chaperone proteins play a vital role inprotein folding and other reactions of proteins involoving major conformational change and the molecular details of these processes are discussed in detail in chapter 14. The final chapter describes the centreal importance of protein folding and unfolding reactions in disease and gives claerdefinition of the term 'misfolding'. Studying protein folding in vivo is full of problems and to show how these problems can be overcome in practice, three case studies of three very different types of protein have been included: the small globular protein apomyoglobin; the fibrous protein collagen;and the membrane protein haemagglutinin.
