scholarly journals The missing link: covalent linkages in structural models

2021 ◽  
Vol 77 (6) ◽  
Author(s):  
Robert A. Nicholls ◽  
Marcin Wojdyr ◽  
Robbie P. Joosten ◽  
Lucrezia Catapano ◽  
Fei Long ◽  
...  
Keyword(s):  
Model Building ◽  
Data Bank ◽  
Deposition Process ◽  
Distance Restraint ◽  
Covalent Linkage ◽  
Atom Pairs ◽  
Main Protease ◽  
Covalently Linked ◽  
Correct Application

Covalent linkages between constituent blocks of macromolecules and ligands have been subject to inconsistent treatment during the model-building, refinement and deposition process. This may stem from a number of sources, including difficulties with initially detecting the covalent linkage, identifying the correct chemistry, obtaining an appropriate restraint dictionary and ensuring its correct application. The analysis presented herein assesses the extent of problems involving covalent linkages in the Protein Data Bank (PDB). Not only will this facilitate the remediation of existing models, but also, more importantly, it will inform and thus improve the quality of future linkages. By considering linkages of known type in the CCP4 Monomer Library (CCP4-ML), failure to model a covalent linkage is identified to result in inaccurate (systematically longer) interatomic distances. Scanning the PDB for proximal atom pairs that do not have a corresponding type in the CCP4-ML reveals a large number of commonly occurring types of unannotated potential linkages; in general, these may or may not be covalently linked. Manual consideration of the most commonly occurring cases identifies a number of genuine classes of covalent linkages. The recent expansion of the CCP4-ML is discussed, which has involved the addition of over 16 000 and the replacement of over 11 000 component dictionaries using AceDRG. As part of this effort, the CCP4-ML has also been extended using AceDRG link dictionaries for the aforementioned linkage types identified in this analysis. This will facilitate the identification of such linkage types in future modelling efforts, whilst concurrently easing the process involved in their application. The need for a universal standard for maintaining link records corresponding to covalent linkages, and references to the associated dictionaries used during modelling and refinement, following deposition to the PDB is emphasized. The importance of correctly modelling covalent linkages is demonstrated using a case study, which involves the covalent linkage of an inhibitor to the main protease in various viral species, including SARS-CoV-2. This example demonstrates the importance of properly modelling covalent linkages using a comprehensive restraint dictionary, as opposed to just using a single interatomic distance restraint or failing to model the covalent linkage at all.

scholarly journals Analysis of the Quality of Macromolecular Structures

2017 ◽  
Author(s):  
Dinakar M. Salunke
Keyword(s):  
Structural Biology ◽  
Model Building ◽  
Structural Data ◽  
Data Bank ◽  
X Ray Crystallography ◽  
Structure Factors ◽  
Scientific Systems ◽  
Published Research

AbstractStructure determination utilizing X-ray crystallography involves collection of diffraction data, determination of initial phases followed by iterative rounds of model building and crystallographic refinement to improve the phases and minimize the differences between calculated and observed structure factors. At each of these stages, a variety of statistical filters exist to ensure appropriate validation. Biologically important observations often come from interpretations of signals that need to be carefully deciphered from noise and therefore human intervention is as important as the automated filters. Currently, all structural data are deposited in the Protein Data Bank and this repository is continuously evolving to incorporate possible new improvements in macromolecular crystallography. The journals that publish data arising from structural studies modulate their policies to take cognizance of new improved methodologies. The PDB and journals have evolved an accepted protocol to ensure the integrity of crystallographic results. As a result, the quality of available data and interpretations are becoming better over the years. However, there have been periodic efforts by some individuals who misuse validation mechanisms to selectively target published research through spurious challenges. These actions do more harm to the field of structural biology and runs counter to their claim to cleanse the system. The scientific systems in structural biology are robust and capable of self-correction and unwarranted vigilantism is counterproductive.

Indicators of Sustainable Development of the Province of Warmia and Mazury in the Environmental Aspect

2016 ◽  
Vol 11 (3) ◽  
pp. 299-309
Author(s):  
Mirosława Witkowska-Dąbrowska
Keyword(s):  
Quality Of Life ◽  
Sustainable Development ◽  
Data Bank ◽  
Local Data ◽  
Indicator Method ◽  
Environmental Aspect ◽  
The Sustainable Development ◽  
Assessment Indicator ◽  
Area Unit

The purpose of this study has been to identify the degree of sustainability in the development of the Province of Warmia and Mazury. The theoretical and empirical investigations were conducted between 2003-2014 based on data from the Local Data Bank. Using a comparative indicator method, 20 indicators were developed, with different directions of preference. The evaluation involves the concept of uniform preference, hence the higher the assessment indicator, the better the situation in the evaluated area unit. Our studies on the sustainable development of the Province of Warmia and Mazury suggest that the indicators measuring the environmental dimension and consequently the quality of life of the residents (in this aspect) score higher than the country's average values. It is also optimistic that some progress, however small, can be seen in this area based on the analyzed dynamics of changes.

Virtual Screening, Molecular docking and in-silico ADME-Tox analysis for identification of potential main protease (Mpro) enzyme inhibitors

2020 ◽  
Vol 18 ◽  
Author(s):  
Debadash Panigrahi ◽  
Ganesh Prasad Mishra
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
In Silico ◽  
Data Bank ◽  
Future Research ◽  
Reference Compound ◽  
Unexpected Death ◽  
Main Protease ◽  
In Silico Admet

Objective:: Recent pandemic caused by SARS-CoV-2 described in Wuhan China in December-2019 spread widely almost all the countries of the world. Corona virus (COVID-19) is causing the unexpected death of many peoples and severe economic loss in several countries. Virtual screening based on molecular docking, drug-likeness prediction, and in silico ADMET study has become an effective tool for the identification of small molecules as novel antiviral drugs to treat diseases. Methods:: In the current study, virtual screening was performed through molecular docking for identifying potent inhibitors against Mpro enzyme from the ZINC library for the possible treatment of COVID-19 pandemic. Interestingly, some compounds are identified as possible anti-covid-19 agents for future research. 350 compounds were screened based on their similarity score with reference compound X77 from ZINC data bank and were subjected to docking with crystal structure available of Mpro enzyme. These compounds were then filtered by their in silico ADME-Tox and drug-likeness prediction values. Result:: Out of these 350 screened compounds, 10 compounds were selected based on their docking score and best docked pose in comparison to the reference compound X77. In silico ADME-Tox and drug likeliness predictions of the top compounds were performed and found to be excellent results. All the 10 screened compounds showed significant binding pose with the target enzyme main protease (Mpro) enzyme and satisfactory pharmacokinetic and toxicological properties. Conclusion:: Based on results we can suggest that the identified compounds may be considered for therapeutic development against the COVID-19 virus and can be further evaluated for in vitro activity, preclinical, clinical studies and formulated in a suitable dosage form to maximize their bioavailability.

scholarly journals Cryo-EM model validation recommendations based on outcomes of the 2019 EMDataResource challenge

2021 ◽  
Vol 18 (2) ◽  
pp. 156-164 ◽  
Author(s):  
Catherine L. Lawson ◽  
Andriy Kryshtafovych ◽  
Paul D. Adams ◽  
Pavel V. Afonine ◽  
Matthew L. Baker ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Structure Data ◽  
Model Evaluation ◽  
Data Bank ◽  
High Accuracy ◽  
Atomic Resolution ◽  
Software Developers ◽  
Data Archives ◽  
Modeling Software

AbstractThis paper describes outcomes of the 2019 Cryo-EM Model Challenge. The goals were to (1) assess the quality of models that can be produced from cryogenic electron microscopy (cryo-EM) maps using current modeling software, (2) evaluate reproducibility of modeling results from different software developers and users and (3) compare performance of current metrics used for model evaluation, particularly Fit-to-Map metrics, with focus on near-atomic resolution. Our findings demonstrate the relatively high accuracy and reproducibility of cryo-EM models derived by 13 participating teams from four benchmark maps, including three forming a resolution series (1.8 to 3.1 Å). The results permit specific recommendations to be made about validating near-atomic cryo-EM structures both in the context of individual experiments and structure data archives such as the Protein Data Bank. We recommend the adoption of multiple scoring parameters to provide full and objective annotation and assessment of the model, reflective of the observed cryo-EM map density.

scholarly journals The Use of Model Atmospheres for Temperature-Gravity Calibration

1973 ◽  
Vol 54 ◽  
pp. 173-221
Author(s):  
J. C. Pecker
Keyword(s):  
Model Building ◽  
Stellar Atmosphere ◽  
Line Formation ◽  
Early Type ◽  
New Concepts ◽  
Total Luminosity ◽  
Classical Models ◽  
Early Type Stars ◽  
Two Parameters

Regardless of the degree of elaboration of series of models, just how can they be used for calibration purposes? And how much is this calibration sensitive to the quality of the model theory? These two questions are the basis of our discussion, which covers : I – The general principles of the use of model atmospheres in stellar calibration (1 – The two dimensional classifications; 2 – The use of the total luminosity; 3 – The cases of Vega and Sirius; 4 – The calibration of ST – Teff relation); II – The failures of the two parameters model atmospheres (1 – The observational need for more-than-two-parameters classification; 2 – The abundance of elements, the line formation, and the model atmospheres; 3 – Various sources of unadequacy of models; 4 – Envelopes or shell features; their influence on model-building; 5 – The case of HD 45677. Diagnostic of early-type stars; 6 – Various unexplained spectral features); III – The present state of the model factory (1 – The classical models; 2 – New concepts in the description of a stellar atmosphere; 3 – New approaches in model making; 4 – Conclusions).

scholarly journals Epitaxial growth by monolayer restricted galvanic displacement

2012 ◽  
Vol 77 (9) ◽  
pp. 1239-1242
Author(s):  
Rastko Vasilic
Keyword(s):  
Epitaxial Growth ◽  
Deposition Process ◽  
Scanning Tunneling ◽  
Deposit Morphology ◽  
Galvanic Displacement ◽  
Tunneling Microscopy ◽  
Efficient Tool ◽  
Dimensional Growth ◽  
Key Parameter

The development of a new method for epitaxial growth of metals in solution by galvanic displacement of layers pre-deposited by underpotential deposition (UPD) was discussed and experimentally illustrated throughout the lecture. Cyclic voltammetry (CV) and scanning tunneling microscopy (STM) are employed to carry out and monitor a ?quasi-perfect?, two-dimensional growth of Ag on Au(111), Cu on Ag(111), and Cu on Au(111) by repetitive galvanic displacement of underpotentially deposited monolayers. A comparative study emphasizes the displacement stoichiometry as an efficient tool for thickness control during the deposition process and as a key parameter that affects the deposit morphology. The excellent quality of layers deposited by monolayer-restricted galvanic displacement is manifested by a steady UPD voltammetry and ascertained by a flat and uniform surface morphology maintained during the entire growth process.

scholarly journals Can We Still Trust Docking Results? An Extension of the Applicability of DockBench on PDBbind Database

2019 ◽  
Vol 20 (14) ◽  
pp. 3558 ◽  
Author(s):  
Giovanni Bolcato ◽  
Alberto Cuzzolin ◽  
Maicol Bissaro ◽  
Stefano Moro ◽  
Mattia Sturlese
Keyword(s):  
Protein Complexes ◽  
Scoring Function ◽  
Data Bank ◽  
The Self ◽  
Protein Families ◽  
Docking Protocol ◽  
Multiple Structures ◽  
Huge Impact ◽  
Ligand Conformation

The number of entries in the Protein Data Bank (PDB) has doubled in the last decade, and it has increased tenfold in the last twenty years. The availability of an ever-growing number of structures is having a huge impact on the Structure-Based Drug Discovery (SBDD), allowing investigation of new targets and giving the possibility to have multiple structures of the same macromolecule in a complex with different ligands. Such a large resource often implies the choice of the most suitable complex for molecular docking calculation, and this task is complicated by the plethora of possible posing and scoring function algorithms available, which may influence the quality of the outcomes. Here, we report a large benchmark performed on the PDBbind database containing more than four thousand entries and seventeen popular docking protocols. We found that, even in protein families wherein docking protocols generally showed acceptable results, certain ligand-protein complexes are poorly reproduced in the self-docking procedure. Such a trend in certain protein families is more pronounced, and this underlines the importance in identification of a suitable protein–ligand conformation coupled to a well-performing docking protocol.

scholarly journals Gamma heavy chain disease: rapid, sustained response to cyclophosphamide and prednisone

Blood ◽  
1975 ◽  
Vol 46 (1) ◽  
pp. 1-9 ◽  
Author(s):  
RM Lyons ◽  
H Chaplin ◽  
TW Tillack ◽  
PW Majerus
Keyword(s):  
Molecular Weight ◽  
Heavy Chain ◽  
Keratoconjunctivitis Sicca ◽  
Coombs Test ◽  
Serum Complement ◽  
Covalent Linkage ◽  
Covalently Linked ◽  
Polypeptide Chains ◽  
Heavy Chain Disease ◽  
Low Serum

Abstract A patient, CAL, with gamma heavy chain disease is presented who has had a complete remission lasting over 2 yr with combination chemotherapy consisting of pulsatile cyclophosphamide and prednisone. The patient exhibited many features of an atuoimmune process including a vasculitis, low serum complement levels, a positive antiglobulin (Coombs) test, Raynaud's phenomenon, and keratoconjunctivitis sicca. The CAL paraprotein was found to have several previously undescribed characteristics. It reacted with antisera to Fd, Fab, and Fab', suggesting that most of the Fd portion of the molecule was intace. CAL protein consists of two polypeptide chains of molecular weight 49,000 covalently linked to form a dimer of 95,000 molecular weight. The covalent linkage suggests that the hinge region of this gamma heavy chain is intact.

Numerical study on structures formed by the deposition and solidification of a single molten droplet

2020 ◽  
Vol 98 (10) ◽  
pp. 907-916
Author(s):  
Wenbin Li ◽  
Ying Zhang ◽  
Yue Chen ◽  
Peisheng Li ◽  
Chunhong Ma
Keyword(s):  
Cooling Rate ◽  
Numerical Study ◽  
Deposition Process ◽  
Droplet Deformation ◽  
Molten Droplet ◽  
Front Tracking Method ◽  
Parametric Studies ◽  
Dynamic Metrics ◽  
Formed Structure

The formed structure is of importance in determining the surface quality of a component made by droplet-based 3D printing. In the present work, the molten droplet solicitation process was simulated under an axisymmetric system where the smallest length scale and time scale were fully resolved. Evolutions of sharp droplet interfaces were captured through the front tracking method. Parametric studies have been carried out to explore how the dynamic metrics, which include the Ohnesorge number (Oh) and Weber number (We), can affect the structure of depositing droplet. The effect of the superheat parameter on the cooling rate was also investigated in the final section. Numerical results show that the inertial resisting force is critical dynamics in the variation of horizontal dimensionless length at the early deposition process. Three levels of Oh numbers and stages of We numbers were classified according to the deformation behavior. Flattening degree under different Oh number and We number cases were both fitted well by the exponential function. This paper also reveals that the variation law of the cooling rate and solidification time is affected by the superheat parameter, resulting in a feasible and promising method to predict droplet deformation time through the fully resolved numerical simulations during the manufacturing process.

scholarly journals Analysis of the velocity diagrams of impellers of centrifugal compressor stages after the preliminary design

2018 ◽  
Vol 245 ◽  
pp. 04004 ◽  
Author(s):  
Aleksandr Drozdov ◽  
Alexey Rekstin
Keyword(s):  
Centrifugal Compressor ◽  
Three Dimensional ◽  
Flow Path ◽  
Preliminary Design ◽  
Flow Paths ◽  
Design Program ◽  
Three Stages ◽  
Correct Application ◽  
Development Laboratory

Preliminary design is an important stape in the development of centrifugal compressors and compressor stages. Basically for this purpose, various recommendations on the choice of the flow path dimensions are applied. Researchers of the Research and Development Laboratory “Gas dynamics of turbomachines” prof. Yu.B. Galerkin and A.F. Rekstin analyzed and summarized the dimensions of flow paths of 124 impellers. On the basis of this analysis, formulas were proposed for choosing the flow path dimensions of the centrifugal compressor stages, which were included in the preliminary design program. The formulas used are designed for relative Mach number of 0.7 and isentropic coefficient of 1.4. The correct application of these formulas for other Mach numbers and isentropic coefficient required development of an appropriate approach and algorithm for adjusting the height of the impeller blades at the outlet. Calculations of gas-dynamic characteristics using the Universal Modeling Method showed the need for selecting a coefficient that takes into account the influence of viscosity to obtain the required pressure characteristics of the compressor stage. This problem was also solved in the program of preliminary design. To check the quality of preliminary design, the results were verified using a non-viscous quasi-three-dimensional calculation program. Three stages were designed for parameters different to those used for development of preliminary design formulas. Analysis of the velocity diagrams of the impeller blades and distribution of meridional velocities showed good results of the preliminary design.

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