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Self‐Assembly of Bent‐Core Nematics in Nanopores
No full textBent-core nematic liquid crystals exhibit unique properties, including giantflexoelectricity and polar electro-optic responses, making them ideal forenergy conversion and electro-optic applications. When confined innanopores, they can stabilize chiral nanostructures, enhance polar order, andenable defect-driven switching – offering potential in nanofluidics, sensing,and adaptive optics. The thermotropic ordering of the bent-core dimer CB7CBconfined in anodic aluminum oxide (AAO) and silica membranes withprecisely engineered cylindrical nanochannels – ranging from just a fewnanometers to several hundred nanometers–is examined. These well-alignednanochannels enable high-resolution polarimetry studies of opticalanisotropy, revealing how geometric confinement affects molecularorganization and phase behavior. Under weak confinement, CB7CB forms alayered heterophase structure, with nematic, splay-bent, and twist-bentheliconical phases likely arranged concentrically. As confinement increases, aLandau-de Gennes analysis shows that ordered phases are suppressed,leaving only a paranematic phase under strong spatial constraints.Remarkably, temperature-dependent changes in optical birefringence underconfinement closely resemble those seen under applied electric fields,revealing a parallel between geometric and electro-optic effects. Overall, thiswork demonstrates how nanoconfinement allows one to systematically tailorthe self-assembly and optical behavior of bent-core nematics, enabling novelfunctionalities in responsive and anisotropic materials
Structural Implications of Missense Point Mutations in Shwachman–Bodian–Diamond Syndrome Protein (SBDS): A Combined SAXS/MD Investigation
No full textShwachman–Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by pleiotropic phenotypes, including pancreatic insufficiency, skeletal abnormalities, and bone marrow dysfunction. Notably, patients with SDS exhibit an increased risk of developing myelodysplastic syndrome and leukemia. In this study, we employed a combination of comparative molecular dynamics (MD) simulations and small-angle X-ray scattering (SAXS)-based analysis to investigate the Shwachman–Bodian–Diamond syndrome protein (SBDS). Specifically, we explored the molecular basis of the syndrome by examining the conformational dynamics of a set of missense mutants of SBDS in comparison to those of the wild-type (WT) protein. Our observations suggest that different mutations may impact (i) the interaction of SBDS with the ribosome, (ii) the binding of SBDS to Elongation Factor-Like 1 (EFL1), and (iii) the SBDS rearrangements coupled to EFL1 binding. Extensive MD simulations, with a total simulation time of 17 μs, revealed variations in the interdomain flexibility of SBDS, which are consistent with previously published affinity data and the new SAXS experimental data presented here. We propose a structural rationale behind the previously reported weak interaction of mutants I167T, R175W, and I212T with EFL1. Additionally, SAXS data indicate that R19Q, I167T, and R175W mutants exhibit altered relative abundances of SBDS conformational states in solution, further supporting our computational results. Overall, our integrated computational and experimental approach provides a comprehensive understanding of how specific mutations in SBDS alter its structural dynamics and binding interactions. These insights enhance our broader understanding of SBDS function and its role in ribosome biogenesis
Allergen-induced structural rearrangements in IgE: insights from SAXS and molecular dynamics
No full textThe initiation of allergic responses critically depends on the recognition of an allergenic epitope by the paratope of IgE antibodies. While previous structural studies have focused on recombinant fragments or engineered forms of IgE, the structure of full-length IgE in its native state remains poorly understood. In this study, we investigate the conformational changes of a native murine IgE (2F5), both in its free form and upon binding to the Hevea brasiliensis allergen profilin (Hev b 8). Small-angle X-ray scattering (SAXS) data reveal that unbound IgE adopts an extended conformation with open Fab arms. However, when it binds to profilin, it transitions to a more compact arrangement characterized by closer proximity of the arms. Molecular dynamics (MD) simulations of the Fab region further identified conformational rearrangements upon allergen binding, including a twisting motion and partial disruption of interactions between the naturally paired heavy and light chains. These findings indicate that there may be allosteric communication between Fab and Fc regions, even in the absence of a hinge region, which is not present in IgE. Overall, this study provides valuable insights into the dynamic structural properties of native IgE and enhances our understanding of the molecular mechanisms underlying allergen recognition
Search for resonances decaying to an anomalous jet and a Higgs boson in proton-proton collisions at = 13 TeV
No full textThis paper presents a search for new physics through the process where a new massive particle, X, decays into a Higgs boson and a second particle, Y. The Higgs boson subsequently decays into a bottom quark-antiquark pair, reconstructed as a single large-radius jet. The decay products of Y are also assumed to produce a single large-radius jet. The identification of the Y particle is enhanced by computing the anomaly score of its candidate jet using an autoencoder, which measures deviations from typical QCD multijet jets. This allows a simultaneous search for multiple Y decay scenarios within a single analysis. In the main benchmark process, Y is a scalar particle that decays into WW. Two other benchmark processes are also considered, where Y is a scalar particle decaying into a light quark-antiquark pair, or into a top quark-antiquark pair. The last benchmark considers Y as a hadronically decaying top quark, arising from the decay of a vector-like quark into a top quark and a Higgs boson. Data recorded by the CMS experiment at a center-of-mass energy of 13 TeV in 20162018, and corresponding to an integrated luminosity of 138 fb, are analyzed. No significant excess is observed, and upper limits on the benchmark signal cross section for various masses of X and Y, at 95% confidence level, are placed
Structural Biology in Action: Investigating EGFR Mutations in Lung Cancer and Engineering Biosynthetic Enzymes
No full textThis thesis explores the role of structural biology in understanding protein function, with a primary focus on EGFR mutations in NSCLC (Part I) and a secondary focus on enzyme engineering for biotechnological applications (Part II). Part I of this thesis investigates how EGFR kinase domain mutations alter protein stability and inhibitor sensitivity through computational modelling, providing insights into drug resistance mechanisms and treatment outcomes in NSCLC patients. Additionally, it examines the role of Molecular Tumor Boards (MTB) in guiding targeted therapies for patients with rare or complex mutational profiles, not only limited to EGFR, but also includes ALK, BRAF MEK and other genes, highlighting the clinical implications of structural insights. Part II of this thesis shifts to an experimental structural approach, focusing its application on protein engineering and enzymatic function. It explores the structural characterization and engineering of a plant polyketide synthase for the biosynthesis of methylated flavonoids, an area of interest for pharmaceutical applications. Additionally, it investigates the substrate specificity and catalytic mechanisms of two bacterial O-methyltransferases, shedding light on their potential in biocatalysis.Whether in assisting precision cancer therapies or engineering enzymes for biocatalysis, the ability to decode protein structures remains a cornerstone of scientific discovery. The studies in this thesis also underscore the complementary roles of computational and experimental methods in structural biology, demonstrating how theoretical predictions and empirical observations together enhance our understanding of protein function, ultimately advancing both fundamental science and its translational applications
Combined in situ X-ray diffraction and tomography study on the evolution of the microstructure in 316L stainless steel foams during compression
No full textThe evolution of the microstructure in 316L stainless steel foams with three different degrees of porosity during compression was studied in situ using the combination of synchrotron X-ray tomography and diffraction line profile analysis. The former and the latter techniques were applied for the investigation of the change of the porosity and the defect structure in the walls, respectively. The stress-strain curves of the foams up to a compressive strain of 0.6 can be divided into three stages irrespectively of the degree of porosity. In the first and third stages, hardening was observed while in the intermediate second stage, a stress drop occurred due to cracking. The evolution of the dislocation density in the walls was similar for all initial porosities: it increased from (2–3) × 10 m to (14–17) × 10 m. The relationship between relative stress and relative density can not be described with traditional models, since the walls consist of spherical particles in the present foams while the former models assumed that the walls comprise rods of equal cross-section. It was revealed that in the first stage of compression (up to the strain of 0.2–0.25) the wall hardening due to the increase of the dislocation density gave similar or higher contribution to increase of the flow stress than that caused by the reduction of porosity due to densification
FLASHlab@PITZ: Eine vielseitig verwendbare Plattform für Bestrahlungen mit Elektronen bei konventionellen und ultrahohen Dosisraten
No full textEinleitung:Am Photo-Injektor-Teststand bei DESY in Zeuthen (PITZ) wurde in den letzten Jahren die Beschleunigeranlage ausgebaut, um Bestrahlungen von biologischen Proben in der R&D Plattform FLASHlab@PITZ mit Elektronen bei einer Strahlenergie bis zu 22 MeV zu ermöglichen [1,2]. Der verfügbare Parameterraum dieser Anlage ist einzigartig und ermöglicht Bestrahlungen bei konventionellen Dosisraten und ultrahohen Dosisraten, weit über den bisherigen Stand der Technik hinaus (Tab. 1). Das ultimative Ziel ist es, den sogenannten FLASH Effekt nachzuweisen und zu optimieren. Dieser besagt, dass bei Bestrahlungen mit ultrahohen Dosisraten (UHDR mit >40 Gy/s) Nebeneffekte, bei gleichbleibender Tumorkontrolle, drastisch reduziert werden können.Material & Methoden:Hier geben wir einen Überblick über die für den Betrieb wichtigen Technologien:• Der PITZ Beschleuniger wurde um eine spezielle Strahlführung erweitert (Abb. 1), die Elektronenpakete für die Bestrahlung im Experimentierbereich zur Verfügung stellt. Neben Magneten für die Strahlführung und -formung enthält diese Komponenten zur Diagnose und ein Kicker-System, mit der beliebige transversale Intensitätsverteilungen erzielt werden können.• Hinter einem Strahlaustrittsfenster wurde ein Experimentierbereich eingerichtet, welcher unterschiedliche Aufbauten beherbergen kann. Standard sind hier ein Roboterarm zur Bestrahlung von in vitro Proben und ein System zur Bestrahlung von Kleintieren. Spezielle Apparaturen können bei Bedarf eingebaut werden.• Zur Überwachung der applizierten Strahlendosen gibt es verschiedene Dosimetrie-Systeme, unter anderem Gafchromische Filme, Diamantdetektoren, Ionisationskammern und Lumineszenzdetektoren.• Die vorhandene Infrastruktur wird durch ein Bio-Labor in unmittelbarer Nähe abgerundet, welches neben Arbeitsbereichen zur Präparation und Analyse von Experimenten, Aufzucht- und Haltungsräume für Zebrafische und Mäuse enthält.Ergebnisse:Nach der Fertigstellung Anfang 2025 wurde die neue Strahlführung in Betrieb genommen und erste Bestrahlungsexperimente durchgeführt. Nach Transport des ~20 MeV Elektronenstrahls wurden die erreichbaren Strahldurchmesser am Austrittsfenster im Bereich von Submillimeter bis etwa 20 mm dokumentiert und mit Strahldynamiksimulationen verglichen. Die Bestrahlungsfelder hinter dem Austrittsfenster wurden dosimetrisch vermessen und mit Monte-Carlo Simulationen verglichen.Zusammenfassung:FLASHlab@PITZ ist eine neue, äußerst flexible Plattform für Bestrahlungsexperimente, die am DESY in Zeuthen aufgebaut wurde. Ziel ist die umfassende Untersuchung von Bestrahlungen mit ultrahohen Dosisraten zur systematischen Erforschung des FLASH Effekts
Bispecific Thio‐Linked Disaccharides as Inhibitors of Pseudomonas Aeruginosa Lectins LecA (PA‐IL) and LecB (PA‐IIL): Dual‐Targeting Strategy
No full textPseudomonas aeruginosa is a prevalent opportunistic human pathogen, particularly associated with cystic fibrosis. Among its virulence factors are the LecA and LecB lectins. Both lectins play an important role in the adhesion to the host cells and display cytotoxic activity. In this study, we successfully synthesized hardly hydrolysable carbohydrate ligands targeting these pathogenic lectins, including two bispecific glycans. The interactions between LecA/LecB lectins and synthetic glycans were evaluated using hemagglutination (yeast agglutination) inhibition assays, comparing their efficacy with corresponding monosaccharides. Additionally, the binding affinities of bispecific glycans were assessed using isothermal titration calorimetry (ITC). Structural insight into the lectin-ligand interaction was obtained by determining the crystal structures of LecA/LecB lectins in complex with one of the bispecific ligands using X ray crystallography. This comprehensive investigation into the inhibitory potential of synthetic glycosides against P. aeruginosa lectins sheds light on their potential application in antimicrobial therapy
Structure-Guided Engineering of a Bacterial Sesterterpene Synthase for Sesterviridene Diversification
No full textTerpene synthases produce a remarkable structural diversity from acyclic precursors through complex carbocation cascades. Here, we report the crystal structure of the bacterial sesterterpene synthase StvirS bound to geranylfarnesyl thiopyrophosphate (GFSPP), revealing a preorganized active site that enforces a defined folding of the C25 backbone. Guided by this structure, active-site engineering at 11 positions yielded 23 enzyme variants and 13 new sesterterpenes. Specific substitutions altered reaction trajectories, stereochemistry, or induced premature termination, emphasizing the sensitivity of StvirS to subtle structural changes. Isotopic labeling established the absolute configurations of 11 products and experimentally confirmed a conserved cyclization pathway. These results illustrate how precise noncovalent interactions govern terpene biosynthesis and highlight the promise of structure-based design to reprogram terpene cyclase reactivity
Virtual fragment screening for DNA repair inhibitors in vast chemical space
No full textFragment-based screening can catalyze drug discovery by identifying novel scaffolds, but this approach is limited by the small chemical libraries studied by biophysical experiments and the challenging optimization process. To expand the explored chemical space, we employ structure-based docking to evaluate orders-of-magnitude larger libraries than those used in traditional fragment screening. We computationally dock a set of 14 million fragments to 8-oxoguanine DNA glycosylase (OGG1), a difficult drug target involved in cancer and inflammation, and evaluate 29 highly ranked compounds experimentally. Four of these bind to OGG1 and X-ray crystallography confirms the binding modes predicted by docking. Furthermore, we show how fragment elaboration using searches among billions of readily synthesizable compounds identifies submicromolar inhibitors with anti-inflammatory and anti-cancer effects in cells. Comparisons of virtual screening strategies to explore a chemical space of 1022 compounds illustrate that fragment-based design enables enumeration of all molecules relevant for inhibitor discovery. Virtual fragment screening is hence a highly efficient strategy for navigating the rapidly growing combinatorial libraries and can serve as a powerful tool to accelerate drug discovery efforts for challenging therapeutic targets