The function of enzymatic proteins is given by their ability to bind specific small molecules into their active sites. These sites can often be found in pockets on a hypothetical boundary between the protein and its environment. Detection, analysis, and visualization of pockets find its use in protein engineering and drug discovery. Many definitions of pockets and algorithms for their computation have been proposed. Kawabata and Go defined them as the regions of empty space into which a small spherical probe can enter but a large probe cannot and developed programs that can compute their approximate shape. In this article, this definition was slightly modified in order to capture the existence of large internal holes, and a Voronoi-based method for the computation of the exact shape of these modified regions is introduced. The method first puts a finite number of large probes on the protein exterior surface and then, considering both large probes and atomic balls as obstacles for the small probe, the method computes the exact shape of the regions for the small probe. This is all achieved with Voronoi diagrams, which help with the safe navigation of spherical probes among spherical obstacles. Detected regions are internally represented as graphs of vertices and edges describing possible movements of the center of the small probe on Voronoi edges. The surface bounding each region is obtained from this representation and used for visualization, volume estimation, and comparison with other approaches. © 2019 Wiley Periodicals, Inc.
Motivation: Studying the transport paths of ligands, solvents, or ions in transmembrane proteins and proteins with buried binding sites is fundamental to the understanding of their biological function. A detailed analysis of the structural features influencing the transport paths is also important for engineering proteins for biomedical and biotechnological applications. Results: CAVER Analyst 2.0 is a software tool for quantitative analysis and real-time visualization of tunnels and channels in static and dynamic structures. This version provides the users with many new functions, including advanced techniques for intuitive visual inspection of the spatiotemporal behavior of tunnels and channels. Novel integrated algorithms allow an efficient analysis and data reduction in large protein structures and molecular dynamic simulations. Availability and implementation: CAVER Analyst 2.0 is a multi-platform standalone Java-based application. Binaries and documentation are freely available at www.caver.cz. Supplementary information: Supplementary data are available at Bioinformatics online.
Geometric models of molecular structures are often described as a set of balls, where balls represent individual atoms. The ability to describe and explore the empty space among these balls is important, e.g., in the analysis of the interaction of enzymes with substrates, ligands and solvent molecules. Voronoi diagrams from the field of computational geometry are often used here, because they provide a mathematical description of how the whole space can be divided into regions assigned to individual atoms. This paper introduces a combination of two different types of Voronoi diagrams into a new hybrid Voronoi diagram - one part of this diagram belongs to the additively weighted (aw-Voronoi) diagram and the other to the power diagram. The boundary between them is controlled by a user-defined constant (the probe radius). Both parts are computed by different algorithms, which are already known. The reduced aw-Voronoi diagram is then obtained by removing the power diagram part from the hybrid diagram. Reduced aw-Voronoi diagrams are perfectly tailored for the analysis of dynamic molecular structures, their computation is faster and storage requirements are lower than in the case of complete aw-Voronoi diagrams. Here, we showed their application to key proteins in cancer research such as p53 and ARID proteins as case study. We identified a biologically relevant cavity in p53 structural ensembles generated by molecular dynamics simulations and analyzed its accessibility, attesting the potential of our approach. This method is relevant for cancer research since it permits to depict a dynamical view of cavities and pockets in proteins that could be affected by mutations in the disease. Our approach opens novel prospects for the study of cancer-related proteins by molecular simulations and the identification of novel targets for drug design.
- MeSH
- algoritmy MeSH
- ligandy MeSH
- proteiny chemie MeSH
- simulace molekulární dynamiky * MeSH
- vazebná místa MeSH
- Publikační typ
- časopisecké články MeSH
UNLABELLED: The transport of ligands, ions or solvent molecules into proteins with buried binding sites or through the membrane is enabled by protein tunnels and channels. CAVER Analyst is a software tool for calculation, analysis and real-time visualization of access tunnels and channels in static and dynamic protein structures. It provides an intuitive graphic user interface for setting up the calculation and interactive exploration of identified tunnels/channels and their characteristics. AVAILABILITY AND IMPLEMENTATION: CAVER Analyst is a multi-platform software written in JAVA. Binaries and documentation are freely available for non-commercial use at http://www.caver.cz.
Průvodce EU
84 s. : il. ; 24 cm
Formou otázek a obsáhlých odpovědí se čtenáři nabízí možnost seznámit se se základními integračními principy uplatňovanými v institucionálním rámci Evropské unie. Nejdříve je pojednáno souhrnné téma struktury politických orgánů a vznik a průběh rozhodovacích procesů. Následují diskuze na hospodářská témata. Řeší se otázky Měnové unie a eura. Jsou probírány oblasti zemědělství, regionálního rozvoje a životního prostředí. Pozornosti neuniká ani sociální politika, otázky zaměstnanosti, školství a kultury a bezpečnosti a zahraniční politiky. Zvláštní kapitola je věnována vzájemnému vztahu České republiky a Evropské Unie.