Including residual contact information into replica-exchange MD simulations significantly enriches native-like conformations

Proteins are complex biomolecules which perform critical tasks in living organisms. Knowledge of a protein’s structure is essential for understanding its physiological function in detail. Despite the incredible progress in experimental techniques, protein structure determination is still expensive, time-consuming, and arduous. That is why computer simulations are often used to complement or interpret experimental data. Here, we explore how in silico protein structure determination based on replica-exchange molecular dynamics (REMD) can benefit from including contact information derived from theoretical and experimental sources, such as direct coupling analysis or NMR spectroscopy. To reflect the influence from erroneous and noisy data we probe how false-positive contacts influence the simulated ensemble. Specifically, we integrate varying numbers of randomly selected native and non-native contacts and explore how such a bias can guide simulations towards the native state. We investigate the number of contacts needed for a significant enrichment of native-like conformations and show the capabilities and limitations of this method. Adhering to a threshold of approximately 75% true-positive contacts within a simulation, we obtain an ensemble with native-like conformations of high quality. We find that contact-guided REMD is capable of delivering physically reasonable models of a protein’s structure

"Deutsche Kultur" und Werbung: Studien zur Geschichte der Wirtschaftswerbung von 1918 bis 1945

Die Arbeit präsentiert die Geschichte der modernen Wirtschaftswerbung in der ersten Hälfte des 20. Jahrhunderts und zeigt, dass Werbung trotz kultureller Barrieren die Alltagswelten der Deutschen kolonialisierte und Einfluss auf die "deutsche Kultur" nahm. Die Arbeit zeigt, dass das Konstrukt der "deutschen Kultur" nicht ausschließlich durch die bürgerliche Hochkultur definiert wurde, sondern zunehmend auch durch Einflüsse der Konsumkultur bestimmt war. Die Bilderwelten der Werbung prägten nationale Ikonen, schufen (bspw. durch Leuchtwerbung) modifizierte "Oberflächen" und Raumwahrnehmungen, ebenso wie die Logik der Marktdifferenzierung und des Marketing soziale Interaktionen als auch die politische Kommunikation (Hitler als Marke) zu bestimmen begann. Diese Entwicklung verlief nicht konfliktfrei. Sowohl die Debatten über Werbung als auch die direkte Konfrontation zwischen Kulturkritikern und Werbern verdeutlichen den massiven Zusammenprall zweier Mentalitäten, die den Konflikt von traditionellem zünftigem Denken, hochkultureller Repräsentation sowie einer vermeintlich authentischen Ästhetik des Inhalts auf der einen Seite und einer "Welt des Scheins" und einer Ästhetik der äußeren Form auf der anderen Seite hervortreten ließ. In dieser Debatte spielte eine Frage eine zentrale Rolle: inwieweit Kapitalismus, Marktwirtschaft, Konsum und die Ästhetik der modernen Lebenswelt mit ihrer spezifischen (werblichen) Oberflächenstruktur mit Vorstellungen "des Deutschen" zu vereinbaren waren.This dissertation offers a history of modern commercial advertising during the first half of the twentieth century and demonstrates that despite cultural barriers, advertising colonized the everyday world of Germans and began to encroach upon "German culture". The work shows that the construct of "German culture" was not only defined by bourgeois high culture, but rather increasingly by factors from consumer culture. The imagery of advertising shaped national icons, created modified "surfaces" (for example, through illuminated ad media) and perceptions of space. Likewise, the logic of market differentiation and marketing began to determine social interactions as well as political communication (Hitler branding). This development did not progress without conflict: Debates surrounding both advertising as well as the direct confrontation between cultural critics and advertisers make clear that there was a massive collision between two mentalities. This allowed a conflict to emerge between traditional, guild thinking, high cultural representations and a putatively authentic aesthetics of content, on the one hand, and on the other hand, a "world of appearances" and aesthetic of the exterior form. One question in particular played a central role in this debate, namely: the extent to which capitalism, the market economy, consumption and the aesthetics of the modern Lebenswelt with its specific (commercial) texture were in accord with ideas of "Germanness.

The Trimeric Major Capsid Protein of Mavirus is stabilized by its Interlocked N-termini Enabling Core Flexibility for Capsid Assembly

Icosahedral viral capsids assemble with high fidelity from a large number of identical buildings blocks. The mechanisms that enable individual capsid proteins to form stable oligomeric units (capsomers) while affording structural adaptability required for further assembly into capsids are mostly unknown. Understanding these mechanisms requires knowledge of the capsomers’ dynamics, especially for viruses where no additional helper proteins are needed during capsid assembly like for the Mavirus virophage that despite its complexity (triangulation number T = 27) can assemble from its major capsid protein (MCP) alone. This protein forms the basic building block of the capsid namely a trimer (MCP$_{3}$) of double-jelly roll protomers with highly intertwined N-terminal arms of each protomer wrapping around the other two at the base of the capsomer, secured by a clasp that is formed by part of the C-terminus. Probing the dynamics of the capsomer with HDX mass spectrometry we observed differences in conformational flexibility between functional elements of the MCP trimer. While the N-terminal arm and clasp regions show above average deuterium incorporation, the two jelly-roll units in each protomer also differ in their structural plasticity, which might be needed for efficient assembly. Assessing the role of the N-terminal arm in maintaining capsomer stability showed that its detachment is required for capsomer dissociation, constituting a barrier towards capsomer monomerisation. Surprisingly, capsomer dissociation was irreversible since it was followed by a global structural rearrangement of the protomers as indicated by computational studies showing a rearrangement of the N-terminus blocking part of the capsomer forming interface

CoCoNet—boosting RNA contact prediction by convolutional neural networks

Co-evolutionary models such as direct coupling analysis (DCA) in combination with machine learning (ML) techniques based on deep neural networks are able to predict accurate protein contact or distance maps. Such information can be used as constraints in structure prediction and massively increase prediction accuracy. Unfortunately, the same ML methods cannot readily be applied to RNA as they rely on large structural datasets only available for proteins. Here, we demonstrate how the available smaller data for RNA can be used to improve prediction of RNA contact maps. We introduce an algorithm called CoCoNet that is based on a combination of a Coevolutionary model and a shallow Convolutional Neural Network. Despite its simplicity and the small number of trained parameters, the method boosts the positive predictive value (PPV) of predicted contacts by about 70% with respect to DCA as tested by cross-validation of about eighty RNA structures. However, the direct inclusion of the CoCoNet contacts in 3D modeling tools does not result in a proportional increase of the 3D RNA structure prediction accuracy. Therefore, we suggest that the field develops, in addition to contact PPV, metrics which estimate the expected impact for 3D structure modeling tools better. CoCoNet is freely available and can be found at https://github.com/KIT-MBS/coconet

"Deutsche Kultur" und Werbung – Studien zur Geschichte der Wirtschaftswerbung von 1918 bis 1945

This dissertation offers a history of modern commercial advertising during the first half of the twentieth century and demonstrates that despite cultural barriers, advertising colonized the everyday world of Germans and began to encroach upon “German culture”. The work shows that the construct of “German culture” was not only defined by bourgeois high culture, but rather increasingly by factors from consumer culture. The imagery of advertising shaped national icons, created modified “surfaces” (for example, through illuminated ad media) and perceptions of space. Likewise, the logic of market differentiation and marketing began to determine social interactions as well as political communication (Hitler branding). This development did not progress without conflict: Debates surrounding both advertising as well as the direct confrontation between cultural critics and advertisers make clear that there was a massive collision between two mentalities. This allowed a conflict to emerge between traditional, guild thinking, high cultural representations and a putatively authentic aesthetics of content, on the one hand, and on the other hand, a “world of appearances” and aesthetic of the exterior form. One question in particular played a central role in this debate, namely: the extent to which capitalism, the market economy, consumption and the aesthetics of the modern Lebenswelt with its specific (commercial) texture were in accord with ideas of “Germanness.

Maxent-Stress Optimization of 3D Biomolecular Models

Knowing a biomolecule\u27s structure is inherently linked to and a prerequisite for any detailed understanding of its function. Significant effort has gone into developing technologies for structural characterization. These technologies do not directly provide 3D structures; instead they typically yield noisy and erroneous distance information between specific entities such as atoms or residues, which have to be translated into consistent 3D models. Here we present an approach for this translation process based on maxent-stress optimization. Our new approach extends the original graph drawing method for the new application\u27s specifics by introducing additional constraints and confidence values as well as algorithmic components. Extensive experiments demonstrate that our approach infers structural models (i.e., sensible 3D coordinates for the molecule\u27s atoms) that correspond well to the distance information, can handle noisy and error-prone data, and is considerably faster than established tools. Our results promise to allow domain scientists nearly-interactive structural modeling based on distance constraints