Software Algorithms For Design Of Symmetric Protein Complexes Applied To Cryo Electron Microscopy Scaffolds And Antibody Nanoparticles
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Software Algorithms For Design Of Symmetric Protein Complexes Applied To Cryo Electron Microscopy Scaffolds And Antibody Nanoparticles
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Author : Ivan Vulovic
language : en
Publisher:
Release Date : 2020
Software Algorithms For Design Of Symmetric Protein Complexes Applied To Cryo Electron Microscopy Scaffolds And Antibody Nanoparticles written by Ivan Vulovic and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2020 with Genomics categories.
Characterization Design And Application Of Natural And Engineered Symmetric Protein Complexes
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Author : Yuxi Liu
language : en
Publisher:
Release Date : 2018
Characterization Design And Application Of Natural And Engineered Symmetric Protein Complexes written by Yuxi Liu 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.
We frequently find proteins exist in oligomeric forms in nature. The abundance of dimers, trimers and tetramers with cyclic or dihedral symmetries in the Protein Data Bank is a good testimony. Even more, it is not rare to find proteins form highly ordered, symmetric, large complexes. These oligomeric forms are usually essential for their functions. Ferritin forms an octahedral cage with 24 subunits to store iron; some virus capsid proteins assemble into icosahedral cages; vaults, which are large dihedral particles widely conserved in eukaryotes, have biological functions yet to be discovered. These fascinating structures inspire three types of questions: How do individual subunits interact form such symmetric complexes? How can we reproduce such complexes with protein engineering? How do we put engineered symmetric protein complexes to application? My thesis work consists of projects addressing all three questions. My first project, described in Chapter 1, concerns bacterial microcompartments (MCP), which are large proteinaceous organelles enclosed by an icosahedral or pseudo-icosahedral shell. MCPs usually enclose special metabolic pathways that are inefficient or toxic in the cytosol. To do so, MCPs must form a sealed barrier with its shell proteins. It was hypothesized that at least one type of the proteins forming the shell of MCPs has to be pentameric instead of hexameric. Indeed, we proved that the BMV proteins, a family of protein highly conserved in MCP operons, formed pentamers in solution. Together with other crystallographic evidence, we conclude BMV proteins form pentamers to cap and seal the MCP shell. In addition to MCPs, I worked on another natural oligomeric protein, bactofilin. Bactofilins are fiber-forming proteins that are widely conserved among bacteria. These proteins have roles in diverse biological functions including but not limited to cell motility, cell wall synthesis and modification. Chapter 2 describe my preliminary biochemical and structural work on bactofilins. Next, I moved on to symmetry-based engineering protein complexes. In Chapter 3, I included a recent review paper on the theory and successes in symmetry-based protein engineering that I participated in preparing. Designed complexes need to be validated at high resolution with X-ray crystallography, but for a long time, the low yield and solubility of the designs complicated their validation. In Chapter 4, we show that mutating solvent-exposed side chains to charged amino acids improved the solubility of a previously low yield tetrahedral design and enabled validation by crystallography. Next, I advanced to a bigger challenge in designing symmetric nanoparticles--icosahedral particles. Icosahedral particles are made up of 60 asymmetric units, as compared to 12 in tetrahedral particles, making them much more difficult to design with accuracy. I was able to validate three different icosahedral design with crystallography, making them the largest designed protein assemblies ever crystallized to date. This work is described in Chapter 5. Additionally, I have made other independent design efforts, one to combine DNA and protein as building materials to design tetrahedral complexes, another to design protein sheets with layer group symmetry. These efforts are documented in Chapter 6.I In the last chapter, I utilized the validated tetrahedral designs as a scaffold in cryo-electron microscope (cryo-EM) for small targets. Despite recent advancements in cryo-EM techniques, small targets remain difficult. By arranging small targets around tetrahedral particles, we can overcome the size limit and provide multiple views to alleviate the commonly seen orientation preference. My project used a type of versatile adaptor protein, designed ankyrin repeat proteins (DARPins), to connect the tetrahedral particles to the imaging targets. We show that the resulting construct is amenable to structural analysis by single particle cryo-EM, allowing us to identify and solve the structure of the attached DARPin at near-atomic detail. The result demonstrates that proteins considerably smaller than the theoretical limit of 50 kDa for cryo-EM can be visualized clearly when arrayed in a rigid fashion on a symmetric designed protein scaffold. Because the amino acid sequence of a DARPin can be chosen to confer tight binding to various other proteins, the system provides a future route for imaging diverse macromolecules, potentially broadening the application of cryo-EM to proteins of typical size in the cell. In conclusion, my thesis work contributes to the understanding of natural oligomeric complexes, expands our capacity in designing symmetric assemblies, and puts forward an example of a useful application of the designed assemblies.
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.
Symmetric Protein Assembly
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Author : Jennifer Erin Padilla
language : en
Publisher:
Release Date : 2003
Symmetric Protein Assembly written by Jennifer Erin Padilla and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2003 with categories.
Deciphering Protein Complex Structures From Cryo Electron Microscopy Maps Using Deep Learning
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Author : Jonas Pfab
language : en
Publisher:
Release Date : 2020
Deciphering Protein Complex Structures From Cryo Electron Microscopy Maps Using Deep Learning written by Jonas Pfab 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.
Information about macromolecular structure of protein complexes such as SARS-CoV-2, and related cellular and molecular mechanisms can assist the search for vaccines and drug development processes. To obtain such structural information, we present DeepTracer, a fully automatic deep learning-based method for fast de novo multi-chain protein complex structure determination from high-resolution cryo-electron microscopy (cryo-EM) density maps. We applied DeepTracer on a previously published set of 476 raw experimental density maps and compared the results with a current state of the art method. The residue coverage increased by over 30% using DeepTracer and the RMSD value improved from 1.29Å to 1.18Å. Additionally, we applied DeepTracer on a set of 62 coronavirus-related density maps, among them 10 with no deposited structure available in EMDataResource. We observed an average residue match of 84% with the deposited structures and an average RMSD of 0.93Å. Additional tests with related methods further exemplify DeepTracer's competitive accuracy and efficiency of structure modeling. DeepTracer allows for exceptionally fast computations, making it possible to trace around 60,000 residues in 350 chains within only two hours. The web service is globally accessible at https://deeptracer.uw.edu.
Protein Complex Structure Determination Guided By Low Resolution Cryo Electron Microscopy Maps
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Author : Daniel P. Farrell
language : en
Publisher:
Release Date : 2021
Protein Complex Structure Determination Guided By Low Resolution Cryo Electron Microscopy Maps written by Daniel P. Farrell and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2021 with categories.
Cryo-electron microscopy of protein complexes often leads to moderate resolution maps (4-8 Ã ), with visible secondary structure elements but poorly resolved loops, making model-building challenging. In the absence of high-resolution structures of homologues, only coarse-grained structural features are typically inferred from these maps, and it is often impossible to assign specific regions of density to individual protein subunits. This dissertation describes a new method for overcoming these difficulties that integrates predicted residue distance distributions from a deep-learned convolutional neural network, computational protein folding using Rosetta, and automated EM-map-guided complex assembly. We will show how this method performs on a diverse benchmarking dataset in addition to describing how it was used to build models for three difficult protein complexes that would have been impossible to solve without this software. We anticipate that our approach will be broadly useful for cryoEM structure determination of large complexes containing many subunits for which there are no homologues of known structure.
Structural Dna Nanotechnology
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Author : Nadrian C. Seeman
language : en
Publisher: Cambridge University Press
Release Date : 2015
Structural Dna Nanotechnology written by Nadrian C. Seeman and has been published by Cambridge University Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2015 with Computers categories.
Written by the founder of the field, this is a comprehensive and accessible introduction to structural DNA nanotechnology.
Development Of Structure Based Computational Methods For Prediction And Design Of Protein Protein Interactions
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Author : Brian Gregory Pierce
language : en
Publisher:
Release Date : 2008
Development Of Structure Based Computational Methods For Prediction And Design Of Protein Protein Interactions written by Brian Gregory Pierce and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2008 with categories.
Abstract: Protein-protein interactions play a key role in the functioning of cells and pathways, and understanding these interactions on a physical and structural level can help greatly in developing therapeutics for diseases. The large amount of protein structures available presents an immense opportunity to model and predict protein interactions using computational techniques. Here we describe the development of algorithms to predict protein complex structures (referred to as protein docking) and to design proteins to improve their interaction affinities. We also present experimental results validating our protein design approach. The protein docking work we present includes the symmetric multimer docking program M-ZDOCK as well as ZRANK which rescores docking predictions using a weighted potential. Both programs have been successful when applied to docking benchmarks and in the CAPRI experiment. In addition, we have used the M-ZDOCK program to produce a tetrameric model for a disease-associated protein, the latent nuclear antigen of the Kaposi's sarcoma-associated herpesvirus. We have also developed a protein design algorithm to improve the binding between two proteins, given their complex structure This was applied to a T cell receptor (TCR) to enhance its binding to the Major Histocompatibility Complex and peptide. Several of the point mutations predicted by our algorithm were verified experimentally to bind several times stronger than wild type; we then combined these mutations to produce a TCR with approximately 100-fold affinity improvement. Further testing of combinations of TCR point mutations has led to striking results regarding the kinetics and cooperativity of the mutations. Finally, we have used our protein design algorithm to predict designability of protein complexes from the Protein Data Bank, and identified the complex between CD4 and HIV gp120 as a target for future structure-based design efforts. Preliminary results for this project are given.
Membrane Protein Crystallization
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Author :
language : en
Publisher: Academic Press
Release Date : 2009-05-29
Membrane Protein Crystallization written by and has been published by Academic Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2009-05-29 with Science categories.
This volume of Current Topics in Membranes focuses on Membrane Protein Crystallization, beginning with a review of past successes and general trends, then further discussing challenges of mebranes protein crystallization, cell free production of membrane proteins and novel lipids for membrane protein crystallization. This publication also includes tools to enchance membrane protein crystallization, technique advancements, and crystallization strategies used for photosystem I and its complexes, establishing Membrane Protein Crystallization as a needed, practical reference for researchers.
Single Particle Cryo Electron Microscopy
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Author : Joachim Frank
language : en
Publisher: World Scientific Publishing Company
Release Date : 2017-12-31
Single Particle Cryo Electron Microscopy written by Joachim Frank and has been published by World Scientific Publishing Company this book supported file pdf, txt, epub, kindle and other format this book has been release on 2017-12-31 with Electron microscopy categories.
The book reproduces 55 of more than 300 articles written by the author, representing milestones in methods development of single-particle cryo-EM as well as important results obtained by this technique in the study of biological macromolecules and their interactions. Importantly, neither symmetries nor ordered arrangements (as in two-dimensional crystals, helical assemblies, icosahedral viruses) are required. Although the biological applications are mainly in the area of ribosome structure and function, the elucidation of membrane channel structures and their activation and gating mechanisms are represented, as well. The book is introduced by a commentary that explains the original development of concepts, describes the contributions of the author's colleagues and students, and shows how challenges were overcome as the technique matured. Along the way, the ribosome served as an example for a macromolecule with intricate structure and conformational dynamics that pose challenges for three-dimensional visualization. Toward the end of the book -- bringing us to the present time -- molecular structures with near-atomic resolution are presented, and a novel type of computational analysis, manifold embedding, is introduced. Single-particle cryo-EM is currently revolutionizing structural biology, presenting a powerful alternative to X-ray crystallography as a means to solve the structure of biological macromolecules. The book presents in one place a number of articles containing key advances in mathematical and computational methods leading up to the present time. Secondly, the development of the technique over the years is reflected by ever-expanding discoveries in the field of ribosome structure and function. Thirdly, as all histories of ideas, the history of concepts pertaining to this new method of visualization is fascinating all in itself.