Abstract: Much of our understanding of protein function arises from the cellular context in which the protein operates. While two proteins may be functionally linked in a variety of ways, the most direct way for them to interact is through physical recognition of the protein surface followed by a binding event. If the function of a single protein can be understood in terms of its interactions, then the function of a biological system as a whole can be viewed through the network of protein interactions. I use structure-driven approaches to gain additional insight into the organization of protein interaction networks by showing distinct differences between transient and obligate protein interactions. This important distinction can be detected on a purely structural level by comparing the pair-wise contact frequencies between different types of atoms at the protein complex interface. On the functional level, the distinction can be made by looking at the curated ontology annotations. Proteins involved in transient and obligate interactions have been subject to different levels of evolutionary pressure and traces of these differences can be detected by considering their evolutionary histories. Residues in the interfaces of obligate complexes tend to evolve at a relatively slower rate, allowing them to co-evolve with their interacting partners. In contrast, the plasticity inherent in transient interactions leads to an increased rate of substitution for the interface residues and leaves little or no evidence of correlated mutations. Recent advances in high-throughput proteomic technologies combined with computational approaches have identified large numbers of putative novel interactions. However both experimental and computational approaches tend to do better identifying components of large obligate complexes, while fleeting interactions crucial in systems such as signaling cascades and immune response are harder to predict. To this end, I developed new representations of protein structure and derived empirical potentials for protein-protein docking, improving on our ability to predict the complex structures of transient complexes from individually crystallized components.

Given the immense progress achieved in elucidating protein-protein complex structures and in the field of protein interaction modeling, there is great demand for a book that gives interested researchers/students a comprehensive overview of the field. This book does just that. It focuses on what can be learned about protein-protein interactions from the analysis of protein-protein complex structures and interfaces. What are the driving forces for protein-protein association? How can we extract the mechanism of specific recognition from studying protein-protein interfaces? How can this knowledge be used to predict and design protein-protein interactions (interaction regions and complex structures)? What methods are currently employed to design protein-protein interactions, and how can we influence protein-protein interactions by mutagenesis and small-molecule drugs or peptide mimetics?The book consists of about 15 review chapters, written by experts, on the characterization of protein-protein interfaces, structure determination of protein complexes (by NMR and X-ray), theory of protein-protein binding, dynamics of protein interfaces, bioinformatics methods to predict interaction regions, and prediction of protein-protein complex structures (docking and homology modeling of complexes, etc.) and design of protein-protein interactions. It serves as a bridge between studying/analyzing protein-protein complex structures (interfaces), predicting interactions, and influencing/designing interactions.

The number of protein sequences grows each year, yet the number of structures deposited in the Protein Data Bank remains relatively small. The importance of protein structure prediction cannot be overemphasized, and this volume is a timely addition to the literature in this field. Protein Structure Prediction: Methods and Protocols is a departure from the normal Methods in Molecular Biology series format. By its very nature, protein structure prediction demands that there be a greater mix of theoretical and practical aspects than is normally seen in this series. This book is aimed at both the novice and the experienced researcher who wish for detailed inf- mation in the field of protein structure prediction; a major intention here is to include important information that is needed in the day-to-day work of a research scientist, important information that is not always decipherable in scientific literature. Protein Structure Prediction: Methods and Protocols covers the topic of protein structure prediction in an eclectic fashion, detailing aspects of pred- tion that range from sequence analysis (a starting point for many algorithms) to secondary and tertiary methods, on into the prediction of docked complexes (an essential point in order to fully understand biological function). As this volume progresses, the authors contribute their expert knowledge of protein structure prediction to many disciplines, such as the identification of motifs and domains, the comparative modeling of proteins, and ab initio approaches to protein loop, side chain, and protein prediction.

This book is indexed in Chemical Abstracts ServiceThe interactions of proteins with other molecules are important in many cellular activities. Investigations have been carried out to understand the recognition mechanism, identify the binding sites, analyze the the binding affinity of complexes, and study the influence of mutations on diseases. Protein interactions are also crucial in structure-based drug design.This book covers computational analysis of protein-protein, protein-nucleic acid and protein-ligand interactions and their applications. It provides up-to-date information and the latest developments from experts in the field, using illustrations to explain the key concepts and applications. This volume can serve as a single source on comparative studies of proteins interacting with proteins/DNAs/RNAs/carbohydrates and small molecules.

This book is about protein structural bioinformatics and how it can help understand and predict protein function. It covers structure-based methods that can assign and explain protein function based on overall folds, characteristics of protein surfaces, occurrence of small 3D motifs, protein-protein interactions and on dynamic properties. Such methods help extract maximum value from new experimental structures, but can often be applied to protein models. The book also, therefore, provides comprehensive coverage of methods for predicting or inferring protein structure, covering all structural classes from globular proteins and their membrane-resident counterparts to amyloid structures and intrinsically disordered proteins. The book is split into two broad sections, the first covering methods to generate or infer protein structure, the second dealing with structure-based function annotation. Each chapter is written by world experts in the field. The first section covers methods ranging from traditional homology modelling and fold recognition to fragment-based ab initio methods, and includes a chapter, new for the second edition, on structure prediction using evolutionary covariance. Membrane proteins and intrinsically disordered proteins are each assigned chapters, while two new chapters deal with amyloid structures and means to predict modes of protein-protein interaction. The second section includes chapters covering functional diversity within protein folds and means to assign function based on surface properties and recurring motifs. Further chapters cover the key roles of protein dynamics in protein function and use of automated servers for function inference. The book concludes with two chapters covering case studies of structure prediction, based respectively on crystal structures and protein models, providing numerous examples of real-world usage of the methods mentioned previously. This book is targeted at postgraduate students and academic researchers. It is most obviously of interest to protein bioinformaticians and structural biologists, but should also serve as a guide to biologists more broadly by highlighting the insights that structural bioinformatics can provide into proteins of their interest.

The protein structure seems to be the materialization of the secret of Nature. The structures of proteins seem to be at the first glance the completely random arrangements of the ribbon-like polypeptide chain. The short visual analysis reveals the existence of some ordered fragments called helices or beta-forms. The order may be of two categories: local short range arrangement and multi-units system engaging few ordered fragments into the non-random structural form generation. Majority of the structures are of random form. The question can be asked How random structures are able to participate in quite complicated processes. The search for the method allowing prediction the structure on the basis of amino acid sequence has longer than 40 years history. The progress in this discipline is measured every second year in CASP (Critical Assessment of Structure Prediction) and CAPRI (Critical Assessment of Protein Interaction). This progress is difficult to be recognized as significant. The methods applied for structure prediction treat the structure as the main goal to be reached. Another interpretation is presented in this volume of Recent Advances in Structural Bioinformatics. The different point of view shall be defined before this new strategy may be discussed. The assumption is that the Nature is interested in making the organism to be active. The organism requires many processes to be run properly, in the correct moment, with the appropriate speed and in the correct place. This large set of conditions may be achieved only when all elements participating in the processes called life are precisely well defined in respect to their duties (understood as biological function). The assumption is that the proteins are tools to perform particular jobs. The job of high specificity (the participation in particular process) performed with high precision makes the proteins unique and highly specialized. The search for protein structure shall be changed into the search for the biological function. Assume that the particular biological function is necessary. Particular structure making possible the expected process is the research object for bioinformatics. The protein structure problem can be expressed as follows: Let me know the expected function construction of the tool ensuring the expected function will be the output. The papers presented in this volume undertake attempt to solve the protein structure problem taking the biological function as the main point characteristic for proteins in respect to all other (organic and inorganic molecules) chemical compounds. This is why the review of the methods oriented on protein-protein interaction is presented in the Chapter 1 (In-silico docking: predicting protein-protein interactions - Marcin Król, Alexander L. Tournier, Paul A. Bates). The static and dynamic models have been described there to search for structural elements making the proteins able to generate the protein-protein complexes which are also of high specificity. This is why the method enabling the recognition of biological function of protein is presented in Chapter 2 (Proteins functional sites recognition based on geometric hashing methods - Maurizio Di Stefano, Giovanni Minervini, Fabio Polticelli). The critical elements of proteins responsible for interaction with ligands (also of high specificity) are described as the discrimination criteria for proteins similarities ensuring their biological activity. This is why the influence of ligands on the biological function and protein structure is described in Chapter 3 (Self-assembled organic molecules as non-standard protein ligands experimental and computational studies - Barbara Stopa, Pawel Spólnik, Leszek Konieczny, Barbara Piekarska, Janina Rybarska, Anna Jagusiak, Marcin Król, Irena Roterman). The nice collaboration of experimentalists in immunochemistry with specialists in bioinformatics is described. The modification of the immunoglobulin activity (immunological signal) as dependent on the ligand form is discussed to reveal the structure-to-function relation. This is why the protein structure prediction technique of heuristic character is presented in Chapter 4 (Late stage folding intermediate in silico Irena Roterman, Leszek Konieczny, Michal Brylinski). The model applied attempts to be as close as possible to the experimental observation introducing the protein structure prediction rather as the protein folding simulation implementing the multi-step character of this process. This is why the biological function definition is introduced in Chapter 5 treating the irregularity of hydrophobicity density in protein molecule as the criterion for aim-oriented structural motif (Biological function recognition in silico Irena Roterman, Leszek Konieczny, Michal Brylinski). This is why the active ligand participation in protein folding process is described in the Chapter 6 (Folding process simulated in the presence of specific ligand - Irena Roterman, Leszek Konieczny, Michal Brylinski). The irregularity of hydrophobicity density distribution in protein molecule is assumed to the result of mutual influencing of ligand and folding polypeptide. This ensures also the generation of binding cavity of high specificity. The subject of each paper presented in this volume undertakes the attempt to link the biological function with the structure of protein, which is responsible for particular biological function.

A new perspective on the design of molecular therapeutics is emerging. This new strategy emphasizes the rational complementation of functionality along extended patches of a protein surface with the aim of inhibiting protein/protein interactions. The successful development of compounds able to inhibit these interactions offers a unique chance to selectively intervene in a large number of key cellular processes related to human disease. Protein Surface Recognition presents a detailed treatment of this strategy, with topics including: an extended survey of protein-protein interactions that are key players in human disease and biology and the potential for therapeutics derived from this new perspective the fundamental physical issues that surround protein-protein interactions that must be considered when designing ligands for protein surfaces examples of protein surface-small molecule interactions, including treatments of protein-natural product interactions, protein-interface peptides, and rational approaches to protein surface recognition from model to biological systems a survey of techniques that will be integral to the discovery of new small molecule protein surface binders, from high throughput synthesis and screening techniques to in silico and in vitro methods for the discovery of novel protein ligands. Protein Surface Recognition provides an intellectual “tool-kit” for investigators in medicinal and bioorganic chemistry looking to exploit this emerging paradigm in drug discovery.

A one-stop reference that reviews protein design strategies to applications in industrial and medical biotechnology Protein Engineering: Tools and Applications is a comprehensive resource that offers a systematic and comprehensive review of the most recent advances in the field, and contains detailed information on the methodologies and strategies behind these approaches. The authors—noted experts on the topic—explore the distinctive advantages and disadvantages of the presented methodologies and strategies in a targeted and focused manner that allows for the adaptation and implementation of the strategies for new applications. The book contains information on the directed evolution, rational design, and semi-rational design of proteins and offers a review of the most recent applications in industrial and medical biotechnology. This important book: Covers technologies and methodologies used in protein engineering Includes the strategies behind the approaches, designed to help with the adaptation and implementation of these strategies for new applications Offers a comprehensive and thorough treatment of protein engineering from primary strategies to applications in industrial and medical biotechnology Presents cutting edge advances in the continuously evolving field of protein engineering Written for students and professionals of bioengineering, biotechnology, biochemistry, Protein Engineering: Tools and Applications offers an essential resource to the design strategies in protein engineering and reviews recent applications.