Exploring cavity dynamics in biomolecular systems

Background The internal cavities of proteins are dynamic structures and their dynamics may be associated with conformational changes which are required for the functioning of the protein. In order to study the dynamics of these internal protein cavities, appropriate tools are required that allow rapid identification of the cavities as well as assessment of their time-dependent structures. Results In this paper, we present such a tool and give results that illustrate the applicability for the analysis of molecular dynamics trajectories. Our algorithm consists of a pre-processing step where the structure of the cavity is computed from the Voronoi diagram of the van der Waals spheres based on coordinate sets from the molecular dynamics trajectory. The pre-processing step is followed by an interactive stage, where the user can compute, select and visualize the dynamic cavities. Importantly, the tool we discuss here allows the user to analyze the time-dependent changes of the components of the cavity structure. An overview of the cavity dynamics is derived by rendering the dynamic cavities in a single image that gives the cavity surface colored according to its time-dependent dynamics. Conclusion The Voronoi-based approach used here enables the user to perform accurate computations of the geometry of the internal cavities in biomolecules. For the first time, it is possible to compute dynamic molecular paths that have a user-defined minimum constriction size. To illustrate the usefulness of the tool for understanding protein dynamics, we probe the dynamic structure of internal cavities in the bacteriorhodopsin proton pump

First PACS‐integrated artificial intelligence‐based software tool for rapid and fully automatic analysis of body composition from CT in clinical routine

Background: To externally evaluate the first picture archiving communications system (PACS)-integrated artificial intelligence (AI)-based workflow, trained to automatically detect a predefined computed tomography (CT) slice at the third lumbar vertebra (L3) and automatically perform complete image segmentation for analysis of CT body composition and to compare its performance with that of an established semi-automatic segmentation tool regarding speed and accuracy of tissue area calculation. Methods: For fully automatic analysis of body composition with L3 recognition, U-Nets were trained (Visage) and compared with a conventional image segmentation software (TomoVision). Tissue was differentiated into psoas muscle, skeletal muscle, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). Mid-L3 level images from randomly selected DICOM slice files of 20 CT scans acquired with various imaging protocols were segmented with both methods. Results: Success rate of AI-based L3 recognition was 100%. Compared with semi-automatic, fully automatic AI-based image segmentation yielded relative differences of 0.22% and 0.16% for skeletal muscle, 0.47% and 0.49% for psoas muscle, 0.42% and 0.42% for VAT and 0.18% and 0.18% for SAT. AI-based fully automatic segmentation was significantly faster than semi-automatic segmentation (3 ± 0 s vs. 170 ± 40 s, P < 0.001, for User 1 and 152 ± 40 s, P < 0.001, for User 2). Conclusion: Rapid fully automatic AI-based, PACS-integrated assessment of body composition yields identical results without transfer of critical patient data. Additional metabolic information can be inserted into the patient’s image report and offered to the referring clinicians

Visuelle Analyse atomarer Strukturen basierend auf dem Modell harter Kugeln

Visualization and Analysis of atomic compositions is essential to understand the structure and functionality of molecules. There exist versatile areas of applications, from fundamental researches in biophysics and materials science to drug development in pharmaceutics. For most applications, the hard-sphere model is the most often used molecular model. Although the model is a quite simple approximation of reality, it enables investigating important physical properties in a purely geometrical manner. Furthermore, large data sets with thousands up to millions of atoms can be visualized and analyzed. In addition to an adequate and efficient visualization of the data, the extraction of important structures plays a major role. For the investigation of biomolecules, such as proteins, especially the analysis of cavities and their dynamics is of high interest. Substrates can bind in cavities, thereby inducing changes in the function of the protein. Another example is the transport of substrates through membrane proteins by the dynamics of the cavities. For both, the visualization as well as the analysis of cavities, the following contributions will be presented in this thesis: 1\. The rendering of smooth molecular surfaces for the analysis of cavities is accelerated and visually improved, which allows showing dynamic proteins. On the other hand, techniques are proposed to interactively render large static biological structures and inorganic materials up to atomic resolution for the first time. 2\. A Voronoi-based method is presented to extract molecular cavities. The procedure comes with a high geometrical accuracy by a comparatively fast computation time. Additionally, new methods are presented to visualize and highlight the cavities within the molecular structure. In a further step, the techniques are extended for dynamic molecular data to trace cavities over time and visualize topological changes. 3\. To further improve the accuracy of the approaches mentioned above, a new molecular surface model is presented that shows the accessibility of a substrate. For the first time, the structure and dynamics of the substrate as hard-sphere model is considered for the accessibility computation. In addition to the definition of the surface, an efficient algorithm for its computation is proposed, which additionally allows extracting cavities. The presented algorithms are demonstrated on different molecular data sets. The data sets are either the result of physical or biological experiments or molecular dynamics simulations.Die Visualisierung und Analyse atomarer Strukturen ist essenziell für das Verständnis des Aufbaus und der Funktionsweise von Molekülen. Es gibt vielfältige Anwendungsgebiete, angefangen von Grundlagenforschungen in der Biophysik und den Materialwissenschaften bis hin zur Medikamentenentwicklung in der Pharmazie. Das Modell harter Kugeln, auch Kalottenmodell genannt, ist dabei das am häufigsten verwendete Molekülmodell. Obwohl es ein sehr vereinfachtes Modell ist, ermöglicht es die geometrische Betrachtung wichtiger physikalischer Eigenschaften und erlaubt zudem, große Daten mit Tausenden bis hin zu Millionen von Atomen darzustellen und zu analysieren. Neben einer adequaten und performanten Visualisierung der Daten spielt vor allem die Extraktion von Strukturen eine große Rolle. Bei der Untersuchung von Biomolekülen, wie Proteinen, ist besonders die Analyse und Dynamik der Kavitäten von großem Interesse. In den Kavitäten können Substrate binden, die damit die Funktionsweise eines Proteins ändern, oder sie können durch die Dynamik der Kavitäten durch Membranen transportiert werden. Sowohl für die Visualisierung als auch für die Analyse der Kavitäten werden in dieser Dissertation die folgenden Beiträge geleistet: 1\. Zum einen wird die Darstellung glatter Oberflächen, die sich für die Analyse von Kavitäten eignen, beschleunigt und visuell verbessert, wodurch sie auf dynamische Proteine angewendet werden können. Zum anderen werden Methoden vorgestellt, die erstmals erlauben große statische biologische Strukturen und anorganische Materialien bis auf atomare Auflösung interaktiv darzustellen. 2\. Für die Extraktion von Kavitäten wird ein Voronoi-basiertes Verfahren mit einer hohen geometrischen Genaugkeit bei einer vergleichsweise hohen Geschwindigkeit vorgestellt. Dazu werden neue Methoden präsentiert, welche die Kavitäten innerhalb der molekularen Struktur darstellen und hervorheben. Des Weiteren werden die Methoden für dynamische Daten erweitert, um Kavitäten über die Zeit verfolgen und topologische Veränderungen visualisieren zu können. 3\. Um die Genauigkeit der oben genannten Verfahren weiter voranzutreiben, wird eine neue Moleküloberfläche vorgestellt, welche die erreichbaren Regionen eines Substrates zeigt. Dabei wird erstmals die Struktur und Dynamik des Substrates in Form des Kalottenmodells berücksichtigt. Neben der Definition der Oberfläche wird ein effizienter Algorithmus für dessen Berechnung präsentiert, der es zudem erlaubt Kavitäten zu extrahieren. Die vorgestellten Algorithmen werde an verschiedenen molekularen Daten demonstriert. Die Daten sind das Ergebnis physikalischer und biologischer Experimente oder stammen aus molekularen Simulationen

Where is the West Antarctic Rift System in the Amundsen Sea and Bellingshausen Sea sectors?

The West Antarctic Rift System (WARS) is one of the largest continental rifts globally, but its lateral extent, distribution of local rifts, timing of rifting phases, and mantle processes are still largely enigmatic. It has been presumed that the rift and its crustal extensional processes have widely controlled the history and development of West Antarctic glaciation with an ice sheet of which most is presently based at sub-marine level and which is, therefore, likely to be highly sensitive to ocean warming. While the western domain of the WARS in the Ross Sea has been studied in some detail, only recently have various geophysical and geochemical/thermochronological analyses revealed indications for its eastern extent in the Amundsen Sea and Bellingshausen Sea sectors of the South Pacific realm. The current model, based on these studies and additional data, suggests that the WARS activity included tectonic translateral, transtensional and extensional processes from the Amundsen Sea Embayment to the Bellingshausen Sea region of the southern Antarctic Peninsula. We present the range of existing hypotheses regarding the extent of the eastern WARS as well as published and yet unpublished data that support a conceptual WARS model for the eastern West Antarctica with implications for glacial onset and developments

The extent of the West Antarctic Rift System in the Amundsen Sea and Bellingshausen Sea sectors

The West Antarctic Rift System (WARS) is one of the largest continental rifts globally, but its lateral extent, distribution of local rifts, timing of rifting phases, and mantle processes are still largely enigmatic. It has been presumed that the rift and its crustal extensional processes have widely controlled the history and development of West Antarctic glaciation with an ice sheet of which most is presently based at sub-marine level and which is, therefore, likely to be highly sensitive to ocean warming. While the western domain of the WARS in the Ross Sea has been studied in some detail, only recently have various geophysical and geochemical/thermochronological analyses revealed indications for its eastern extent in the Amundsen Sea and Bellingshausen Sea sectors of the South Pacific realm and in the eastern Marie Byrd Land, Ellsworth Land, Thurston Island and Antarctic Peninsula crustal blocks. One of the current models, based on these studies and additional data, suggests that the WARS activity included tectonic translateral, transtensional and extensional processes from the Amundsen Sea Embayment to the Bellingshausen Sea region of the southern Antarctic Peninsula, basically following the eastward migrating collision of the Phoenix Plate with the Antarctic Plate. We present the range of existing and novel hypotheses regarding the extent of the eastern WARS as well as published and yet unpublished data that support a conceptual WARS model for West Antarctica with implications for glacial onset and developments

Virtual unfolding of folded papyri

The historical importance of ancient manuscripts is unique since they provide information about the heritage of ancient cultures. Often texts are hidden in rolled or folded documents. Due to recent improvements in sensitivity and resolution, spectacular disclosures of rolled hidden texts were possible by X-ray tomography. However, revealing text on folded manuscripts is even more challenging. Manual unfolding is often too risky in view of the fragile condition of fragments, as it can lead to the total loss of the document. X-ray tomography allows for virtual unfolding and enables non-destructive access to hidden texts. We have recently demonstrated the procedure and tested unfolding algorithms on a mockup sample. Here, we present results on unfolding ancient papyrus packages from the papyrus collection of the Musée du Louvre, among them objects folded along approximately orthogonal folding lines. In one of the packages, the first identification of a word was achieved, the Coptic word for “Lord”

Membrane Protein Structure, Function, and Dynamics: a Perspective from Experiments and Theory

Membrane proteins mediate processes that are fundamental for the flourishing of biological cells. Membrane-embedded transporters move ions and larger solutes across membranes; receptors mediate communication between the cell and its environment and membrane-embedded enzymes catalyze chemical reactions. Understanding these mechanisms of action requires knowledge of how the proteins couple to their fluid, hydrated lipid membrane environment. We present here current studies in computational and experimental membrane protein biophysics, and show how they address outstanding challenges in understanding the complex environmental effects on the structure, function, and dynamics of membrane proteins