Computational Design Of Symmetric Protein Complexes With Implications For Vaccine And Biotherapeutic Development
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Computational Design Of Symmetric Protein Complexes With Implications For Vaccine And Biotherapeutic Development
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Author : George Ueda
language : en
Publisher:
Release Date : 2018
Computational Design Of Symmetric Protein Complexes With Implications For Vaccine And Biotherapeutic Development written by George Ueda and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2018 with categories.
Using a newly developed computational docking and scoring method combined with Rosetta two-sided interface design, we demonstrated accurate design of self-assembling oligomeric proteins that exhibit various degrees of symmetry. A set of designs were validated to match their respective models at the atomic-scale and we progressed to functionalize this class of proteins for targeted biological applications. With the unique ability to tailor new protein structures, we span a diversity of controllable geometric arrangements representing a molecular toolkit to probe biological systems at the subnanometer scale. Presented in this dissertation are examples of next-generation vaccine candidates that scaffold entire antigenic complexes, as well as potential biotherapeutics that activate signaling pathways through engagement and tunable clustering of cell surface receptors. These studies showcase the potential for computationally-generated molecules to trigger unique biological responses, providing novel insights, considerations, and future avenues for vaccine and biotherapeutic development across various disease spaces.
Theory Design And Characterization Of Protein Symmetry Combination Materials
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Author : Joshua Laniado
language : en
Publisher:
Release Date : 2020
Theory Design And Characterization Of Protein Symmetry Combination Materials written by Joshua Laniado and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2020 with categories.
ABSTRACT OF THE DISSERTATIONTheory, Design and Characterization of Protein Symmetry Combination Materials by Joshua Laniado Doctor of Philosophy in the Molecular Biology Interdepartmental Doctoral Program: Biochemistry, Biophysics & Structural Biology University of California, Los Angeles, 2020 Professor Todd O. Yeates, Chair Nature has evolved a plethora of sophisticated protein complexes to carry out fundamental biological processes. While most of these exquisite macromolecular machines exhibit complex architectures, many are composed of only a few different types of subunits. Understanding how protein molecules combine to form these remarkable self-assembling structures only makes sense in the light of symmetry. By limiting the number of distinct interactions required between individual subunits, symmetry offers a simpler route for the evolution of supramolecular assemblies such as viral capsids and bacterial microcompartments. Principles of symmetry and self-assembly have invigorated recent efforts in molecular engineering giving rise to a growing suite of novel protein materials such as finite cages and extended crystalline arrays. These designed assemblies are rapidly finding applications in areas as diverse as vaccine design, atomic imaging, enzyme scaffolding and molecular delivery. Despite significant advances in computational approaches and design strategies, constructing these materials remains extremely challenging. Here, we address key experimental and theoretical limitations to improve the prospects for the routine design of novel symmetric protein materials. In Chapter 1, we review current methodologies for designing self-assembling protein nanomaterials. A first approach presented the idea that when two separate symmetric oligomers associate in some geometrically defined way, a structure with higher symmetry can be obtained through self-assembly. There, an alpha-helical linker is used to connect two oligomeric components and to control their relative geometry. A second approach does not involve genetic fusion but relies instead on the computational design of a novel protein-protein interface. After reviewing the successful constructions resulting from both methods, challenges and limitations are discussed. In the fusion approach, the inherent flexibility of the alpha helical linker can lead to the formation of unintended assemblies. Alternatively, the interface design strategy exhibits limited success in predicting viable protein interfaces. The prevalence of such limitations dramatically hinders the creation of novel materials, motivating the development of alternate strategies. In the next chapter, we introduce a new approach for the design of symmetric self-assembling nanomaterials. Building upon the fusion approach, the original alpha-helical linker is replaced with a heterodimeric coiled coil as an attempt to reduce flexibility. Further, the use of a known heterodimeric interface to combine component oligomers alleviates the challenges associated with de novo interface design. Ten symmetric protein cages were designed using this method among which two were structurally characterized. One design assembled as intended while the other crystallized in an alternate form. Geometric distinctions between the two help explain the different degrees of success, leading to crucial lessons and establishing clearer principles for the creation of novel nanoscale protein architectures. While some experimental aspects have been addressed, only a small fraction of the possible design space has been explored. That space, which is anticipated to offer a multitude of symmetry-based combinations, has not been described in theory. In Chapter 3, we articulate all of the possible kinds of protein-based materials that can be created by combining two symmetric oligomers. Specifically, 13 types of cages, 35 types of 2-D layers and 76 types of 3-D crystals are identified as possible targets for design. We lay out a complete rule set for constructing all such symmetry combination materials (SCMs) and introduce a unified system for parameterizing and searching the construction space for each case. This theoretical and computational study provides a blueprint for a blossoming area of macromolecular design. Owing to the complexity and our limited understanding of the rules that govern protein behavior, designing protein-protein interfaces remains challenging. Current approaches rely on empirical or knowledge-based energy functions and optimization algorithms that often fail to produce stable interfaces. On the other hand, there is growing evidence that the database of known protein structures is now sufficiently large to cover the structural landscape of protein interfaces. In Chapter 4, we argue that carefully-selected structural motifs can be used as templates for interface design. We introduce Nanohedra, a fragment-based docking tool that harnesses the power of our theoretical framework to enable the design of all possible SCMs. Prospective designs of symmetric materials are proposed along with a retrospective analysis of recent design studies. In this analysis, our tool recapitulates all successful designs while poorly ranking failed ones. With a user-friendly interface and a unified protocol for symmetric protein design, Nanohedra enables the creation of a universe of novel nanomaterials and opens new avenues for nanobiotechnology.
Protein Self Assembly
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Author : Jennifer J. McManus
language : en
Publisher: Humana
Release Date : 2020-08-08
Protein Self Assembly written by Jennifer J. McManus and has been published by Humana this book supported file pdf, txt, epub, kindle and other format this book has been release on 2020-08-08 with Science categories.
This volume explores experimental and computational approaches to measuring the most widely studied protein assemblies, including condensed liquid phases, aggregates, and crystals. The chapters in this book are organized into three parts: Part One looks at the techniques used to measure protein-protein interactions and equilibrium protein phases in dilute and concentrated protein solutions; Part Two describes methods to measure kinetics of aggregation and to characterize the assembled state; and Part Three details several different computational approaches that are currently used to help researchers understand protein self-assembly. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Thorough and cutting-edge, Protein Self-Assembly: Methods and Protocols is a valuable resource for researchers who are interested in learning more about this developing field.
Mers Cov
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Author : Fang Li
language : en
Publisher: MDPI
Release Date : 2019-12-12
Mers Cov written by Fang Li and has been published by MDPI this book supported file pdf, txt, epub, kindle and other format this book has been release on 2019-12-12 with Science categories.
Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging zoonotic coronavirus. First identified in 2012, MERS-CoV has caused over 2460 infections and a fatality rate of about 35% in humans. Similar to severe acute respiratory syndrome coronavirus (SARS-CoV), MERS-CoV likely originated from bats; however, different from SARS-CoV, which potentially utilized palm civets as its intermediate hosts, MERS-CoV likely transmits to humans through dromedary camels. Animal models, such as humanized mice and nonhuman primates, have been developed for studying MERS-CoV infection. Currently, there are no vaccines and therapeutics approved for the prevention and treatment of MERS-CoV infection, although a number of them have been developed preclinically or tested clinically. This book covers one editorial and 16 articles (including seven review articles and nine original research papers) written by researchers working in the field of MERS-CoV. It describes the following three main aspects: (1) MERS-CoV epidemiology, transmission, and pathogenesis; (2) current progress on MERS-CoV animal models, vaccines, and therapeutics; and (3) challenges and future prospects for MERS-CoV research. Overall, this book will help researchers in the MERS-CoV field to further advance their work on the virus. It also has important implications for other coronaviruses as well as viruses outside the coronavirus family with pandemic potentials.
Computational Pharmaceutics
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Author : Defang Ouyang
language : en
Publisher: John Wiley & Sons
Release Date : 2015-07-20
Computational Pharmaceutics written by Defang Ouyang and has been published by John Wiley & Sons this book supported file pdf, txt, epub, kindle and other format this book has been release on 2015-07-20 with Science categories.
Molecular modeling techniques have been widely used in drug discovery fields for rational drug design and compound screening. Now these techniques are used to model or mimic the behavior of molecules, and help us study formulation at the molecular level. Computational pharmaceutics enables us to understand the mechanism of drug delivery, and to develop new drug delivery systems. The book discusses the modeling of different drug delivery systems, including cyclodextrins, solid dispersions, polymorphism prediction, dendrimer-based delivery systems, surfactant-based micelle, polymeric drug delivery systems, liposome, protein/peptide formulations, non-viral gene delivery systems, drug-protein binding, silica nanoparticles, carbon nanotube-based drug delivery systems, diamond nanoparticles and layered double hydroxides (LDHs) drug delivery systems. Although there are a number of existing books about rational drug design with molecular modeling techniques, these techniques still look mysterious and daunting for pharmaceutical scientists. This book fills the gap between pharmaceutics and molecular modeling, and presents a systematic and overall introduction to computational pharmaceutics. It covers all introductory, advanced and specialist levels. It provides a totally different perspective to pharmaceutical scientists, and will greatly facilitate the development of pharmaceutics. It also helps computational chemists to look for the important questions in the drug delivery field. This book is included in the Advances in Pharmaceutical Technology book series.
Computational Structural Biology
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Author : Torsten Schwede
language : en
Publisher: World Scientific
Release Date : 2008
Computational Structural Biology written by Torsten Schwede and has been published by World Scientific this book supported file pdf, txt, epub, kindle and other format this book has been release on 2008 with Science categories.
This is a comprehensive introduction to Landau-Lifshitz equations and Landau-Lifshitz-Maxwell equations, beginning with the work by Yulin Zhou and Boling Guo in the early 1980s and including most of the work done by this Chinese group led by Zhou and Guo since. The book focuses on aspects such as the existence of weak solutions in multi dimensions, existence and uniqueness of smooth solutions in one dimension, relations with harmonic map heat flows, partial regularity and long time behaviors. The book is a valuable reference book for those who are interested in partial differential equations, geometric analysis and mathematical physics. It may also be used as an advanced textbook by graduate students in these fields.
Lyophilized Biologics And Vaccines
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Author : Dushyant Varshney
language : en
Publisher: Springer
Release Date : 2015-05-19
Lyophilized Biologics And Vaccines written by Dushyant Varshney and has been published by Springer this book supported file pdf, txt, epub, kindle and other format this book has been release on 2015-05-19 with Medical categories.
This book provides a detailed account of the most recent developments, challenges and solutions to seamlessly advance and launch a lyophilized biologics or vaccine product, based on diverse modalities, ranging from antibodies (e.g., monoclonal, fused), complex biologics (e.g., antibody drug conjugate, PEGylated proteins), and vaccines (e.g., recombinant-protein based). The authors adeptly guide the reader through all crucial aspects, from biophysical and chemical stability considerations of proteins, analytical methods, advances in controlled ice nucleation and quality-by-design approaches, alternate drying technology, to latest regulatory, packaging and technology transfer considerations to develop a stable, safe and effective therapeutic protein, vaccine and biotechnology products. Lyophilized Biologics and Vaccines: Modality-Based Approaches is composed of four sections with a total of 17 chapters. It serves as a reference to all critical assessments and steps from early pre-formulation stages to product launch: Provides recent understanding of heterogeneity of protein environment and selection of appropriate buffer for stabilization of lyophilized formulations Details the latest developments in instrumental analysis and controlled ice nucleation technology Explains in-depth lyophilized (or dehydrated) formulation strategies considering diverse modalities of biologics and vaccines, including plasmid DNA and lipid-based therapeutics Details an exhaustive update on quality-by-design and process analytical technology approaches, illustrated superbly by case studies and FDA perspective Provides the latest detailed account of alternate drying technologies including spray drying, bulk freeze-drying and crystallization, supported exceptionally by case studies Provides a step-by-step guide through critical considerations during process scale-up, technology transfer, packaging and drug delivery device selection, for a successful lyophilization process validation, regulatory submission and product launch Chapters are written by one or more world-renowned leading authorities from academia, industry or regulatory agencies, whose expertise cover lyophilization of the diverse modalities of biopharmaceuticals. Their contributions are based on the exhaustive review of literature coupled with excellent hands-on experiences in laboratory or GMP setup, making this an exceptional guide to all stages of lyophilized or dehydrated product development.
Bioinformatics And Systems Biology
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Author : Frederick Marcus
language : en
Publisher: Springer Science & Business Media
Release Date : 2008-07-22
Bioinformatics And Systems Biology written by Frederick Marcus and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2008-07-22 with Science categories.
Collaborative research in bioinformatics and systems biology is a key element of modern biology and health research. This book highlights and provides access to many of the methods, environments, results and resources involved, including integral laboratory data generation and experimentation and clinical activities. Collaborative projects embody a research paradigm that connects many of the top scientists, institutions, their resources and research worldwide, resulting in first-class contributions to bioinformatics and systems biology. Central themes include describing processes and results in collaborative research projects using computational biology and providing a guide for researchers to access them. The book is also a practical guide on how science is managed. It shows how collaborative researchers are putting results together in a way accessible to the entire biomedical community.
Lyophilization Of Biopharmaceuticals
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Author : Henry R. Costantino
language : en
Publisher: Springer Science & Business Media
Release Date : 2005-12-05
Lyophilization Of Biopharmaceuticals written by Henry R. Costantino and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2005-12-05 with Medical categories.
Humans have been experimenting with lyophilization, or freeze-drying, as a method to preserve biological structures for over a thousand years. This comprehensive volume, intended for scientists in both academia and industry, covers a wide range of topics relevant to the formulation of peptide and protein drugs in the freeze-dried state.
Development Of Biopharmaceutical Drug Device Products
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Author : Feroz Jameel
language : en
Publisher: Springer Nature
Release Date : 2020-03-13
Development Of Biopharmaceutical Drug Device Products written by Feroz Jameel and has been published by Springer Nature this book supported file pdf, txt, epub, kindle and other format this book has been release on 2020-03-13 with Medical categories.
The biotechnology/biopharmaceutical sector has tremendously grown which led to the invention of engineered antibodies such as Antibody Drug Conjugates (ADCs), Bispecific T-cell engager (BITES), Dual Variable Domain (DVD) antibodies, and fusion proteins that are currently being used as therapeutic agents for immunology, oncology and other disease conditions. Regulatory agencies have raised the bar for the development and manufacture of antibody-based products, expecting to see the use of Quality by Design (QbD) elements demonstrating an in-depth understanding of product and process based on sound science. Drug delivery systems have become an increasingly important part of the therapy and most biopharmaceuticals for self-administration are being marketed as combination products. A survey of the market indicates that there is a strong need for a new book that will provide “one stop shopping” for the latest information and knowledge of the scientific and engineering advances made over the last few years in the area of biopharmaceutical product development. The new book entitled Development of Biopharmaceutical Drug Device Products is a reference text for scientists and engineers in the biopharmaceutical industry, academia or regulatory agencies. With insightful chapters from experts in the field, this new book reviews first principles, covers recent technological advancements and provides case studies and regulatory strategies relating to the development and manufacture of antibody-based products. It covers topics such as the importance of early preformulation studies during drug discovery to influence molecular selection for development, formulation strategies for new modalities, and the analytical techniques used to characterize them. It also addresses important considerations for later stage development such as the development of robust formulations and processes, including process engineering and modeling of manufacturing unit operations, the design of analytical comparability studies, and characterization of primary containers (pre-filled syringes and vials).Finally, the latter half of the book reviews key considerations to ensure the development and approval of a patient-centered delivery system design. This involves the evolving regulatory framework with perspectives from both the US and EU industry experts, the role of international standards, design control/risk management, human factors and its importance in the product development and regulatory approval process, as well as review of the risk-based approach to bridging between devices used in clinical trials and the to-be-marketed device. Finally, case studies are provided throughout.The typical readership would have biology and/or engineering degrees and would include researchers, scientific leaders, industry specialists and technology developers working in the biopharmaceutical field.