Tyrosine sulfation alters the biological activity of many proteins involved in different physiological and pathophysiological conditions, such as non-specific immune reaction, response to inflammation and ischemia, targeting of leukocytes and stem cells, or the formation of cancer metastases. Tyrosine sulfation is catalyzed by the enzymes tyrosylprotein sulfotransferases (TPST). In this study, we used QM/MM Car-Parrinello metadynamics simulations together with QM/MM potential energy calculations to investigate the catalytic mechanism of isoform TPST-1. The structural changes along the reaction coordinate are analyzed and discussed. Furthermore, both the methods supported the SN2 type of catalytic mechanism. The reaction barrier obtained from CPMD metadynamics was 12.8 kcal mol-1, and the potential energy scan led to reaction barriers of 11.6 kcal mol-1 and 13.7 kcal mol-1 with the B3LYP and OPBE functional, respectively. The comparison of the two methods (metadynamics and potential energy scan) may be helpful for future mechanistic studies. The insight into the reaction mechanism of TPST-1 might help with the rational design of transition-state TPST inhibitors.

• MeSH
• biokatalýza MeSH
• katalytická doména MeSH
• kvantová teorie MeSH
• lidé MeSH
• simulace molekulární dynamiky MeSH
• sulfotransferasy chemie   MeSH
• termodynamika MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• protein-tyrosine sulfotransferase MeSH Prohlížeč
• sulfotransferasy MeSH

Nicotinic acetylcholine receptors (nAChRs) comprise a large and ancient family of allosteric ion channels mediating synaptic transmission. The vast knowledge about nAChRs has become difficult to navigate. NAChRDB is a web-accessible resource of curated residue-level functional annotations of neuromuscular nAChRs. Interactive three-dimensional (3D) visualization and sequence alignment give further context to this rich and growing collection of experimental observations and computational predictions. NAChRDB is freely available at https://crocodile.ncbr.muni.cz/Apps/NAChRDB/, with interactive tutorials and regular updates to the content and web interface. No installation or user registration is required. NAChRDB is accessible through any modern internet browser on desktops and mobile devices. By providing immediate and systematic access to practical knowledge gained through decades of research, NAChRDB represents a powerful educational tool and helps guide discovery by revealing gaps in current knowledge and aiding the interpretation of results of molecular and structural biology experiments or computational studies.

• Publikační typ
• časopisecké články MeSH

Coronavirus disease 2019 (COVID-19) has spread rapidly throughout the globe. The spectrum of disease is broad but among hospitalized patients with COVID-19, respiratory failure from acute respiratory distress syndrome is the leading cause of mortality. There is an urgent need for an effective treatment. The current focus has been developing novel therapeutics, including antivirals, protease inhibitors, vaccines and targeting the overactive cytokine response with anti-cytokine therapy. The overproduction of early response proinflammatory cytokines results in what has been described as a "cytokine storm" is leading eventually to death when the cells fail to terminate the inflammatory response. Accumulating evidence shows that inflammatory cytokines induce selectin ligands that play a crucial role in the pathogenesis of inflammatory diseases by mediating leukocyte migration from the blood into the tissue. Thus, the selectins and selectin ligands represent a promising therapeutic target for the treatment of COVID-19. In this paper, potential pan-selectin inhibitors were identified employing a virtual screening using a docking procedure. For this purpose, the Asinex and ZINC databases of ligands, including approved drugs, biogenic compounds and glycomimetics, altogether 923,602 compounds, were screened against the P-, L- and E-selectin. At first, the experimentally confirmed inhibitors were docked into all three selectins' carbohydrate recognition domains to assess the suitability of the screening procedure. Finally, based on the evaluation of ligands binding, we propose 10 purchasable pan-selectin inhibitors to develop COVID-19 therapeutics.

• Klíčová slova
• COVID-19, docking, pan-selectin inhibitors, selectins, virtual screening,
• MeSH
• antivirové látky chemie   MeSH
• biomimetické materiály chemie   MeSH
• chemické databáze * MeSH
• farmakoterapie COVID-19 * MeSH
• lidé MeSH
• počítačová simulace * MeSH
• preklinické hodnocení léčiv MeSH
• SARS-CoV-2 chemie   metabolismus   MeSH
• selektiny chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• selektiny MeSH

• Publikační typ
• tisková chyba MeSH

Large biomolecular structures are being determined experimentally on a daily basis using established techniques such as crystallography and electron microscopy. In addition, emerging integrative or hybrid methods (I/HM) are producing structural models of huge macromolecular machines and assemblies, sometimes containing 100s of millions of non-hydrogen atoms. The performance requirements for visualization and analysis tools delivering these data are increasing rapidly. Significant progress in developing online, web-native three-dimensional (3D) visualization tools was previously accomplished with the introduction of the LiteMol suite and NGL Viewers. Thereafter, Mol* development was jointly initiated by PDBe and RCSB PDB to combine and build on the strengths of LiteMol (developed by PDBe) and NGL (developed by RCSB PDB). The web-native Mol* Viewer enables 3D visualization and streaming of macromolecular coordinate and experimental data, together with capabilities for displaying structure quality, functional, or biological context annotations. High-performance graphics and data management allows users to simultaneously visualise up to hundreds of (superimposed) protein structures, stream molecular dynamics simulation trajectories, render cell-level models, or display huge I/HM structures. It is the primary 3D structure viewer used by PDBe and RCSB PDB. It can be easily integrated into third-party services. Mol* Viewer is open source and freely available at https://molstar.org/.

• MeSH
• internet MeSH
• konformace proteinů MeSH
• makromolekulární látky chemie   MeSH
• molekulární modely * MeSH
• software * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• makromolekulární látky MeSH

BACKGROUND: Partial atomic charges find many applications in computational chemistry, chemoinformatics, bioinformatics, and nanoscience. Currently, frequently used methods for charge calculation are the Electronegativity Equalization Method (EEM), Charge Equilibration method (QEq), and Extended QEq (EQeq). They all are fast, even for large molecules, but require empirical parameters. However, even these advanced methods have limitations-e.g., their application for peptides, proteins, and other macromolecules is problematic. An empirical charge calculation method that is promising for peptides and other macromolecular systems is the Split-charge Equilibration method (SQE) and its extension SQE+q0. Unfortunately, only one parameter set is available for these methods, and their implementation is not easily accessible. RESULTS: In this article, we present for the first time an optimized guided minimization method (optGM) for the fast parameterization of empirical charge calculation methods and compare it with the currently available guided minimization (GDMIN) method. Then, we introduce a further extension to SQE, SQE+qp, adapted for peptide datasets, and compare it with the common approaches EEM, QEq EQeq, SQE, and SQE+q0. Finally, we integrate SQE and SQE+qp into the web application Atomic Charge Calculator II (ACC II), including several parameter sets. CONCLUSION: The main contribution of the article is that it makes SQE methods with their parameters accessible to the users via the ACC II web application ( https://acc2.ncbr.muni.cz ) and also via a command-line application. Furthermore, our improvement, SQE+qp, provides an excellent solution for peptide datasets. Additionally, optGM provides comparable parameters to GDMIN in a markedly shorter time. Therefore, optGM allows us to perform parameterizations for charge calculation methods with more parameters (e.g., SQE and its extensions) using large datasets.

• Klíčová slova
• Empirical methods, Parameterization, Partial atomic charges, Web service,
• Publikační typ
• časopisecké články MeSH

Protein structural families are groups of homologous proteins defined by the organization of secondary structure elements (SSEs). Nowadays, many families contain vast numbers of structures, and the SSEs can help to orient within them. Communities around specific protein families have even developed specialized SSE annotations, always assigning the same name to the equivalent SSEs in homologous proteins. A detailed analysis of the groups of equivalent SSEs provides an overview of the studied family and enriches the analysis of any particular protein at hand. We developed a workflow for the analysis of the secondary structure anatomy of a protein family. We applied this analysis to the model family of cytochromes P450 (CYPs)-a family of important biotransformation enzymes with a community-wide used SSE annotation. We report the occurrence, typical length and amino acid sequence for the equivalent SSE groups, the conservation/variability of these properties and relationship to the substrate recognition sites. We also suggest a generic residue numbering scheme for the CYP family. Comparing the bacterial and eukaryotic part of the family highlights the significant differences and reveals a well-known anomalous group of bacterial CYPs with some typically eukaryotic features. Our workflow for SSE annotation for CYP and other families can be freely used at address https://sestra.ncbr.muni.cz .

• MeSH
• lidé MeSH
• sekvenční analýza proteinů metody   MeSH
• simulace molekulární dynamiky MeSH
• software * MeSH
• systém (enzymů) cytochromů P-450 chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• systém (enzymů) cytochromů P-450 MeSH

Two citations in the article by Sehnal et al. [(2020), Acta Cryst. D76, 1167-1173] are corrected.

• Klíčová slova
• corrigendum, data delivery, macromolecules, visualization,
• Publikační typ
• tisková chyba MeSH

Biomacromolecular structural data make up a vital and crucial scientific resource that has grown not only in terms of its amount but also in its size and complexity. Furthermore, these data are accompanied by large and increasing amounts of experimental data. Additionally, the macromolecular data are enriched with value-added annotations describing their biological, physicochemical and structural properties. Today, the scientific community requires fast and fully interactive web visualization to exploit this complex structural information. This article provides a survey of the available cutting-edge web services that address this challenge. Specifically, it focuses on data-delivery problems, discusses the visualization of a single structure, including experimental data and annotations, and concludes with a focus on the results of molecular-dynamics simulations and the visualization of structural ensembles.

• Klíčová slova
• browser-based, data delivery, macromolecules, visualization, web-based,
• MeSH
• internet * MeSH
• makromolekulární látky chemie   MeSH
• počítačová grafika * MeSH
• software * MeSH
• uživatelské rozhraní počítače * MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• makromolekulární látky MeSH

3D macromolecular structural data is growing ever more complex and plentiful in the wake of substantive advances in experimental and computational structure determination methods including macromolecular crystallography, cryo-electron microscopy, and integrative methods. Efficient means of working with 3D macromolecular structural data for archiving, analyses, and visualization are central to facilitating interoperability and reusability in compliance with the FAIR Principles. We address two challenges posed by growth in data size and complexity. First, data size is reduced by bespoke compression techniques. Second, complexity is managed through improved software tooling and fully leveraging available data dictionary schemas. To this end, we introduce BinaryCIF, a serialization of Crystallographic Information File (CIF) format files that maintains full compatibility to related data schemas, such as PDBx/mmCIF, while reducing file sizes by more than a factor of two versus gzip compressed CIF files. Moreover, for the largest structures, BinaryCIF provides even better compression-factor ten and four versus CIF files and gzipped CIF files, respectively. Herein, we describe CIFTools, a set of libraries in Java and TypeScript for generic and typed handling of CIF and BinaryCIF files. Together, BinaryCIF and CIFTools enable lightweight, efficient, and extensible handling of 3D macromolecular structural data.

• MeSH
• chemické databáze MeSH
• komprese dat metody   MeSH
• krystalografie metody   MeSH
• makromolekulární látky chemie   ultrastruktura   MeSH
• molekulární modely * MeSH
• software * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• makromolekulární látky MeSH