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Changes in the second edition

The field of proteins is vast, and in the six years that have passed since the publication of the first edition of this book, many exciting discoveries have emerged, covering virtually every topic discussed herein. We have updated all of our discussions accordingly, with emphasis on the following:

Membrane proteins (Chapter 7) – Three-dimensional structures of membrane proteins have always been more difficult to determine compared with the structures of water-soluble proteins. Dramatic progress has been made in structure determination methods, resulting in numerous new structures of highly important membrane proteins, including receptors, channels/transporters, and enzymes. Furthermore, in certain types of membrane proteins, such as GPCRs, the new structures have provided new functional insights. For example, many of the new GPCR structures were determined in a partially- or fully-activated mode. Such structures were almost completely absent when the first edition of this book came out. Accordingly, in the current edition, we are able to elaborate on the activation process of GPCRs. In addition, the availability of new structures of GPCRs belonging to classes B, C and F enables us to describe the features that these proteins share with the more common class A GPCRs, as well as their differences.

Methods for studying proteins (Chapter 3) – Recent technological breakthroughs in cryo-electron microscopy (cryo-EM) and small-angle X-ray scattering (SAXS) are reshaping structural biology. First, thanks to dramatic improvement in the resolution of cryo-EM, scientists have been able to determine the structures of many proteins that are difficult to crystallize and therefore inaccessible to X-ray diffraction (e.g., membrane proteins). Second, cryo-EM and SAXS have facilitated the structural determination of large protein complexes, which are often the proteins’ functional forms. Third, the data extracted from these methods can be used as constraints that guide computational structure prediction of proteins. Thus, the availability of such data has revolutionized the field of computational structure prediction. To reflect these developments, we have expanded Chapter 3 significantly by elaborating on the uses of cryo-EM and SAXS. We also provide an extensive discussion of new hybrid computational methods, which integrate different approaches for the purpose of computational structure prediction.

Enzyme catalysis (Chapter 9) - The relationship between structure and function in proteins reaches its highest level of sophistication in enzymatic catalysis. Enzymes are also a key component in all life-forms, and are involved in virtually all life processes. For this reason, we addressed enzymes and enzymatic catalysis in the first edition, emphasizing their metabolic roles. However, since enzymes are routinely described in biochemistry textbooks, we refrained from elaborating on this topic. Yet, the recent proliferation of structural and biophysical analysis methods has led to a better understanding of the structure, energetics, molecular dynamics, and chemical mechanisms of enzymes. This made it possible in the current edition to apply our physicochemical approach to enzymatic catalysis, as we had done previously for the other aspects of protein structure and function. Thus, we have added a completely new chapter to the book, which provides an extensive description of various aspects of enzymes, including types and classification, metabolic roles, molecular mechanisms, kinetics, energetics, dynamics, the use of cofactors, inhibition, related diseases, engineering, and practical uses in medicine and in other industries. Our discussion of catalytic mechanisms integrates structural, dynamic, and thermodynamic aspects, including quantum phenomena, which are ignored in most textbooks. This comprehensive coverage provides the reader with what we believe is an unprecedented view of enzymes. We decided to make this chapter the last one in the book, as all the important principles of enzymatic catalysis result from phenomena described in the previous chapters: preorganized structure (Chapter 2), dynamic qualities (Chapter 5), and protein-ligand interactions (Chapter 8). Similarly, applications that involve enzymes are also touched on in earlier chapters; for example, enzyme engineering is largely based on general protein engineering and drug design principles, which are described in Chapter 8.

In addition to updating the book and expanding its scope, we also aimed to make it more reader-friendly. Thus, the second edition includes a larger number of figures, and also incorporates two new technical features that make the learning experience more enjoyable and efficient:

1. Animations - Certain processes, such as multistep chemical reactions and conformational changes in macromolecules, are difficult to describe using static images alone. We have therefore created numerous animations of these processes, each of which is linked to the corresponding book page via a QR code, which the reader can scan using a smartphone. Scanning the QR code immediately links the smartphone to the Internet location of the animation, enabling the reader to watch the animation while reading the book.
2. PyMOL session files – The book contains numerous images of 3D protein structures, which are used to explain structural, dynamic, and functional phenomena. While these images are very informative, readers and instructors often wish they could look at the displayed proteins from different angles or use different molecular representations to get a better understanding of the ideas that the image aims to illustrate. PyMOL is free software that can be used to perform such manipulations, provided that the user has a file containing the protein’s 3D coordinates. In the current edition, we provide PyMOL session files (.pse) for many of the structural images in the book. Each session file allows the reader to use PyMOL to open a molecular representation of the protein, exactly as it is shown in the corresponding book image. The reader can then use the representation as a starting point for further changes and manipulations. The provided PyMOL session files include, in most cases, pre-defined elements of the respective proteins (secondary structures, ligands, electrostatic potential maps, annotations of polar interactions, etc.), which make it easier for the readers to manipulate the proteins.

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