scholarly journals DeepTracer for fast de novo cryo-EM protein structure modeling and special studies on CoV-related complexes

2020 ◽  
Vol 118 (2) ◽  
pp. e2017525118
Author(s):  
Jonas Pfab ◽  
Nhut Minh Phan ◽  
Dong Si
Keyword(s):  
Molecular Mechanisms ◽  
De Novo ◽  
Structural Information ◽  
Protein Complexes ◽  
Complex Structure ◽  
Structure Modeling ◽  
Current State ◽  
Average Residue ◽  
Development Processes ◽  
Special Studies

Information about macromolecular structure of protein complexes 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 automated deep learning-based method for fast de novo multichain protein complex structure determination from high-resolution cryoelectron microscopy (cryo-EM) maps. We applied DeepTracer on a previously published set of 476 raw experimental cryo-EM 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 1.29 Å to 1.18 Å. Additionally, we applied DeepTracer on a set of 62 coronavirus-related cryo-EM 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 0.93 Å. 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 2 h. The web service is globally accessible at https://deeptracer.uw.edu.

scholarly journals DeepTracer: Fast Cryo-EM Protein Structure Modeling and Special Studies on CoV-related Complexes

2020 ◽  
Author(s):  
Jonas Pfab ◽  
Nhut Minh Phan ◽  
Dong Si
Keyword(s):  
Molecular Mechanisms ◽  
De Novo ◽  
Structural Information ◽  
Protein Complexes ◽  
Complex Structure ◽  
Structure Modeling ◽  
Density Maps ◽  
Average Residue ◽  
Development Processes ◽  
Special Studies

AbstractInformation 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.

scholarly journals Studying the Structures of Relaxed and Fuzzy Interactions: The Diverse World of S100 Complexes

2021 ◽  
Vol 8 ◽  
Author(s):  
Péter Ecsédi ◽  
Gergő Gógl ◽  
László Nyitray
Keyword(s):  
Neurodegenerative Diseases ◽  
Structural Biology ◽  
Binding Proteins ◽  
Structural Information ◽  
Protein Complexes ◽  
Point Of View ◽  
S100 Proteins ◽  
Current State ◽  
Diverse World

S100 proteins are small, dimeric, Ca2+-binding proteins of considerable interest due to their associations with cancer and rheumatic and neurodegenerative diseases. They control the functions of numerous proteins by forming protein–protein complexes with them. Several of these complexes were found to display “fuzzy” properties. Examining these highly flexible interactions, however, is a difficult task, especially from a structural biology point of view. Here, we summarize the available in vitro techniques that can be deployed to obtain structural information about these dynamic complexes. We also review the current state of knowledge about the structures of S100 complexes, focusing on their often-asymmetric nature.

scholarly journals A new approach to time-resolved X-ray crystallography

2014 ◽  
Vol 70 (a1) ◽  
pp. C1434-C1434
Author(s):  
Briony Yorke ◽  
Arwen Pearson ◽  
Godfrey Beddard ◽  
Robin Owen
Keyword(s):  
Molecular Mechanisms ◽  
Structural Information ◽  
Information Storage ◽  
High Time Resolution ◽  
Time Resolved ◽  
New Approach ◽  
X Ray ◽  
X Ray Crystallography ◽  
Current State ◽  
Initial Results

Time-resolved crystallography is able to provide four-dimensional structural information about short-lived intermediate states, with near-atomic resolution. This information can be used to elucidate molecular mechanisms relevant to areas such as drug-design, chemical and biological sensors, and energy and information storage. The current state of the art time-resolved experiments can reach picosecond time-resolutions using Laue crystallography but such experiments can only be carried out at a few beamlines worldwide.We have developed a new transform time-resolved method that can be performed using a monochromatic beamline at a synchrotron and still achieve high time-resolution, vastly increasing the accessibility of such experiments. Here we present initial results demonstrating the method.

Integrative Structure Modeling: Overview and Assessment

2019 ◽  
Vol 88 (1) ◽  
pp. 113-135 ◽  
Author(s):  
Merav Braitbard ◽  
Dina Schneidman-Duhovny ◽  
Nir Kalisman
Keyword(s):  
Model Building ◽  
Structural Information ◽  
Protein Complexes ◽  
Structure Modeling ◽  
Sources Of Information ◽  
Multiple Sources ◽  
New Era ◽  
Integrative Modeling ◽  
Future Challenges ◽  
Computational Aspects

Integrative structure modeling computationally combines data from multiple sources of information with the aim of obtaining structural insights that are not revealed by any single approach alone. In the first part of this review, we survey the commonly used sources of structural information and the computational aspects of model building. Throughout the past decade, integrative modeling was applied to various biological systems, with a focus on large protein complexes. Recent progress in the field of cryo–electron microscopy (cryo-EM) has resolved many of these complexes to near-atomic resolution. In the second part of this review, we compare a range of published integrative models with their higher-resolution counterparts with the aim of critically assessing their accuracy. This comparison gives a favorable view of integrative modeling and demonstrates its ability to yield accurate and informative results. We discuss possible roles of integrative modeling in the new era of cryo-EM and highlight future challenges and directions.

scholarly journals Generating intrafusal skeletal muscle fibres in vitro: Current state of the art and future challenges

2020 ◽  
Vol 11 ◽  
pp. 204173142098520
Author(s):  
Philip Barrett ◽  
Tom J Quick ◽  
Vivek Mudera ◽  
Darren J Player
Keyword(s):  
Skeletal Muscle ◽  
Muscle Spindle ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Ex Vivo ◽  
Muscle Fibres ◽  
Current State ◽  
Intrafusal Fibres ◽  
Proprioceptive Function

Intrafusal fibres are a specialised cell population in skeletal muscle, found within the muscle spindle. These fibres have a mechano-sensory capacity, forming part of the monosynaptic stretch-reflex arc, a key component responsible for proprioceptive function. Impairment of proprioception and associated dysfunction of the muscle spindle is linked with many neuromuscular diseases. Research to-date has largely been undertaken in vivo or using ex vivo preparations. These studies have provided a foundation for our understanding of muscle spindle physiology, however, the cellular and molecular mechanisms which underpin physiological changes are yet to be fully elucidated. Therefrom, the use of in vitro models has been proposed, whereby intrafusal fibres can be generated de novo. Although there has been progress, it is predominantly a developing and evolving area of research. This narrative review presents the current state of art in this area and proposes the direction of future work, with the aim of providing novel pre-clinical and clinical applications.

ProAffiMuSeq: sequence-based method to predict the binding free energy change of protein–protein complexes upon mutation using functional classification

2019 ◽  
Author(s):  
Sherlyn Jemimah ◽  
Masakazu Sekijima ◽  
M Michael Gromiha
Keyword(s):  
Free Energy ◽  
Protein Interactions ◽  
Large Scale ◽  
Structural Information ◽  
Protein Complexes ◽  
Binding Free Energy ◽  
Complex Structure ◽  
External Validation ◽  
Functional Class ◽  
Supplementary Information

Abstract Motivation Protein–protein interactions are essential for the cell and mediate various functions. However, mutations can disrupt these interactions and may cause diseases. Currently available computational methods require a complex structure as input for predicting the change in binding affinity. Further, they have not included the functional class information for the protein–protein complex. To address this, we have developed a method, ProAffiMuSeq, which predicts the change in binding free energy using sequence-based features and functional class. Results Our method shows an average correlation between predicted and experimentally determined ΔΔG of 0.73 and mean absolute error (MAE) of 0.86 kcal/mol in 10-fold cross-validation and correlation of 0.75 with MAE of 0.94 kcal/mol in the test dataset. ProAffiMuSeq was also tested on an external validation set and showed results comparable to structure-based methods. Our method can be used for large-scale analysis of disease-causing mutations in protein–protein complexes without structural information. Availability and implementation Users can access the method at https://web.iitm.ac.in/bioinfo2/proaffimuseq/. Supplementary information Supplementary data are available at Bioinformatics online.

Crystal structures of Magnaporthe oryzae trehalose-6-phosphate synthase (MoTps1) suggest a model for catalytic process of Tps1

2019 ◽  
Vol 476 (21) ◽  
pp. 3227-3240 ◽  
Author(s):  
Shanshan Wang ◽  
Yanxiang Zhao ◽  
Long Yi ◽  
Minghe Shen ◽  
Chao Wang ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Conformational Changes ◽  
Magnaporthe Oryzae ◽  
Structural Information ◽  
Complex Structure ◽  
Critical Role ◽  
Catalytic Process ◽  
Structural Basis ◽  
Salt Bridges ◽  
Terminal Domain

Trehalose-6-phosphate (T6P) synthase (Tps1) catalyzes the formation of T6P from UDP-glucose (UDPG) (or GDPG, etc.) and glucose-6-phosphate (G6P), and structural basis of this process has not been well studied. MoTps1 (Magnaporthe oryzae Tps1) plays a critical role in carbon and nitrogen metabolism, but its structural information is unknown. Here we present the crystal structures of MoTps1 apo, binary (with UDPG) and ternary (with UDPG/G6P or UDP/T6P) complexes. MoTps1 consists of two modified Rossmann-fold domains and a catalytic center in-between. Unlike Escherichia coli OtsA (EcOtsA, the Tps1 of E. coli), MoTps1 exists as a mixture of monomer, dimer, and oligomer in solution. Inter-chain salt bridges, which are not fully conserved in EcOtsA, play primary roles in MoTps1 oligomerization. Binding of UDPG by MoTps1 C-terminal domain modifies the substrate pocket of MoTps1. In the MoTps1 ternary complex structure, UDP and T6P, the products of UDPG and G6P, are detected, and substantial conformational rearrangements of N-terminal domain, including structural reshuffling (β3–β4 loop to α0 helix) and movement of a ‘shift region' towards the catalytic centre, are observed. These conformational changes render MoTps1 to a ‘closed' state compared with its ‘open' state in apo or UDPG complex structures. By solving the EcOtsA apo structure, we confirmed that similar ligand binding induced conformational changes also exist in EcOtsA, although no structural reshuffling involved. Based on our research and previous studies, we present a model for the catalytic process of Tps1. Our research provides novel information on MoTps1, Tps1 family, and structure-based antifungal drug design.

HAZARD: An Expert System for Risk Assessment of Environmental Chemicals

1987 ◽  
Vol 26 (01) ◽  
pp. 13-23 ◽  
Author(s):  
H. W. Gottinger
Keyword(s):  
Expert System ◽  
Structural Information ◽  
Chemical Carcinogenesis ◽  
Structural Features ◽  
Environmental Chemicals ◽  
Chemical Carcinogens ◽  
Carcinogenic Activity ◽  
Current State ◽  
Structure Activity ◽  
Carcinogenic Potential

AbstractThe purpose of this paper is to report on an expert system in design that screens for potential hazards from environmental chemicals on the basis of structure-activity relationships in the study of chemical carcinogenesis, particularly with respect to analyzing the current state of known structural information about chemical carcinogens and predicting the possible carcinogenicity of untested chemicals. The structure-activity tree serves as an index of known chemical structure features associated with carcinogenic activity. The basic units of the tree are the principal recognized classes of chemical carcinogens that are subdivided into subclasses known as nodes according to specific structural features that may reflect differences in carcinogenic potential among chemicals in the class. An analysis of a computerized data base of known carcinogens (knowledge base) is proposed using the structure-activity tree in order to test the validity of the tree as a classification scheme (inference engine).

STUDY OF THE ORGANIZATION ADAPTIVITY RATE CORRELATION IN RELATION TO ITS INTERNAL INTEGRITY

2020 ◽  
Vol 3 (4) ◽  
pp. 292-304
Author(s):  
Inna O. Hordieieva ◽  
Valentina M. Molokanova
Keyword(s):  
Project Management ◽  
Stable State ◽  
Evolutionary Development ◽  
Current State ◽  
Modern Project ◽  
Development Processes ◽  
Methodological Principles ◽  
Internal Integration ◽  
Strategic Project ◽  
Rate Correlation

The focus of modern project management is increasingly shifting from the management of individual projects to the management of strategic project-oriented development of organizations. Now there is a need to pay more attention to project management as a universal tool for the development of systems at any level. The aim of the article is to study the processes of organization adaptation to constant changes through a synergetic portfolio of projects based on a strategic plan for the development and evolution of the organization. The spiral movement of systems development for studying development processes is considered: the process of transition of an organization from one stable state to another, the process of radical changes that accompanies innovation, as well as the processes of growth and development of crisis phenomena. The methodological principles of the organization evolutionary development management through the implementation of portfolio using its methods and tools are considered. It is proposed to manage the organization evolutionary development by building actions in the form of a synergistic portfolio of appropriate projects content, in order to increase the value of the entire portfolio of projects over the value of individual projects. The synergetic portfolio of projects is seen as a tool for a harmonious transition to the desired evolutionary state, by preserving the internal integrity of the organization and ensuring its sustainability. A mathematical model for estimating the desired properties and relations of the organizational synergetic portfolio of projects is proposed, which allows to determine and minimize the magnitude of the evolutionary goals inconsistency and to stabilize the current state of organization. It is determined that the two main tasks of any organization - external adaptation and internal integration - constantly push the organization to evolutionary development. The article proposes the author's approach to managing the organization evolutionary development through a portfolio of projects identifies indicators of adaptation of the organization to changes in the environment, defines the conditions for maintaining the integrity of the organization in the process of organizational changes.

Rapid Online Buffer Exchange: A Method for Screening of Proteins, Protein Complexes, and Cell Lysates by Native Mass Spectrometry

2019 ◽  
Author(s):  
Zachary VanAernum ◽  
Florian Busch ◽  
Benjamin J. Jones ◽  
Mengxuan Jia ◽  
Zibo Chen ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
High Speed ◽  
Structural Information ◽  
Protein Complexes ◽  
High Sensitivity ◽  
Native Mass Spectrometry ◽  
Structural Features ◽  
Consumer Products ◽  
Cell Lysates ◽  
Protein Expression And Purification

It is important to assess the identity and purity of proteins and protein complexes during and after protein purification to ensure that samples are of sufficient quality for further biochemical and structural characterization, as well as for use in consumer products, chemical processes, and therapeutics. Native mass spectrometry (nMS) has become an important tool in protein analysis due to its ability to retain non-covalent interactions during measurements, making it possible to obtain protein structural information with high sensitivity and at high speed. Interferences from the presence of non-volatiles are typically alleviated by offline buffer exchange, which is timeconsuming and difficult to automate. We provide a protocol for rapid online buffer exchange (OBE) nMS to directly screen structural features of pre-purified proteins, protein complexes, or clarified cell lysates. Information obtained by OBE nMS can be used for fast (<5 min) quality control and can further guide protein expression and purification optimization.

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