Ben-Tal Lab

Proteins are highly complex molecules that are actively involved in the most basic and important aspects of life. These include metabolism, movement, defense, cellular communication, and molecular recognition. Accordingly, protein science is at the very center of biological research, and is applied to disciplines such as medicine, agriculture, biotechnology, and even unconventional warfare. In the last few decades, with the development of accurate and sophisticated means of molecular structure determination, it has become clear that the function of macromolecules in general and of proteins in particular is a direct result of structure and structural dynamics. It has similarly become evident that, to obtain a true understanding of protein function, structure and dynamics, it is necessary to both qualitatively and quantitatively characterize the dominant physical forces that act on proteins at the atomic level. These insights have prompted the emergence of a new field in biological sciences, termed 'structural biophysics'. This book aims to provide the reader with a detailed description of protein structure and dynamics, combined with an in-depth discussion of the relationship between both these aspects and protein function. We approach these topics through the lens of structural biophysics, focusing on the molecular interactions and thermodynamic changes that transpire in highly complex biological systems. There are several types of textbooks describing protein structure and function. Biochemistry textbooks emphasize the functional aspect of proteins and provide a rather general description of structure and the structure-function relationship. Structural biology textbooks provide extensive descriptions of protein structure, and also refer to the structure-function relationship with varying degrees of detail. However, energy-related aspects are often avoided. Molecular biophysics textbooks focus on molecular interactions and thermodynamic aspects of protein structure, but tend not to delve deeply into structural and dynamic aspects, or into the structure-function relationship. Our book refers to all of the aforementioned aspects, and attempts to provide a unified view. Our energy-oriented approach is manifested throughout the book, whether we discuss structure, dynamics, or specific functions of proteins, such as catalysis or signal transduction. An extensive discussion of the energetics of protein structure is also given in a chapter dedicated to this topic. Most textbooks that describe the structure-function relationship in proteins do so by using specific examples or protein types. This approach provides a broad view of protein activity, but may be insufficient to enable the reader to draw general conclusions. Here, when possible, we attempt to provide clear outlines of the very principles of protein action (as we understand them). This is done throughout the book, but particularly in the last three chapters, describing membrane-bound proteins, protein-ligand interactions, and enzyme-mediated catalysis. These topics, as well as any topic involving protein structure and function, are difficult to explain by using text and simple graphics. We therefore use the following means to convey to the reader the full experience of protein science: 1. Numerous high-resolution figures that portray real 3D protein structures. Readers with a professional background in structural biology can also use the (free) PyMOL session files that we provide for each structural figure. These files, which are available online, can be viewed and manipulated using free PyMOL software. 2. Animations of biochemical processes. The animations are fully accessible by QR codes, which can be scanned directly and easily from the book by any smartphone (see more in ‘Changes in the second edition’ below). The central dogma of structural biology is the dependence of function on structure. Yet, some proteins, termed 'intrinsically unstructured proteins' (IUPs), are inherently devoid of a regular three-dimensional structure, and still have numerous functions. IUPs have been studied extensively in the last few years, yet are not mentioned in most textbooks. We dedicate a chapter of the book to these proteins, in order to provide a more complete and realistic view of the proteome, as well as to explore the full repertoire of protein functions. Much of the knowledge on the relationship between protein structure and function became available only with the advent of technologies for the determination or prediction of proteins’ three-dimensional structures. Accordingly, we provide a concise description of the main experimental and computational methods used today for studying protein structure and dynamics. In this respect, we mention various Internet-based resources, such as databases, algorithms, software and webservers, which are widely used and fully accessible to the reader. Moreover, as mentioned above, we emphasize that protein science is not only of academic interest. Indeed, it has been applied in various industrial, medical, and agricultural fields. In our book we discuss three of these applications: the industrial use of enzymes, protein engineering, and the rational design of pharmaceutical drugs that target specific proteins. We believe that our broad coverage of the different facets of protein science make our book relevant to both students and scientists of protein-related fields. Introduction to Proteins: Structure, Function and Motion is intended for various audiences. First, the book can be used by undergraduate or graduate students of biochemistry, structural biology, computational biophysics, bioinformatics, and biotechnology, as an introduction to protein structure. In that sense, it may serve as a standalone textbook for basic- to intermediate-level courses in structural biology. For such purposes, we provide exercises related to theory and practice. Sample answers, as well as a set of PowerPoint slide shows that incorporate the figures presented in this book, are also available for qualifying instructors. Second, we expect that the parts of the book that provide detailed discussions of energetic, dynamic and evolutionary aspects of proteins will be of special interest to post-graduate scientists and industry professionals. To make it easier for these two groups of readers to find their texts of interest, we have, in some cases, separated the basic material from more advanced discussions, by putting the latter in ‘Boxes’. Finally, the book refers to many everyday issues related to proteins and enzymes, such as medical disorders, drugs, toxins, chemical warfare, and animal behavior. We hope that our coverage of these topics will create interest among some non-professional science enthusiasts as well. In this book, we use numerous proteins as examples, demonstrating the various topics and principles discussed. Some proteins are mentioned in several different contexts, to reflect the multiple ways in which proteins can be studied and analyzed. For example, hemoglobin is used to demonstrate quaternary structure, pathologies stemming from structure-altering mutations, and the role of dynamics in allosteric regulation. Another example is the cancer-related protein ras, used to demonstrate different types of post-translational modifications.