New substance library to accelerate the search for active compounds

In order to accelerate the systematic development of drugs, the MX team at the Helmholtz-Zentrum Berlin (HZB) and the Drug Design Group at the University of Marburg have established a new substance library. It consists of 1103 organic molecules that could be used as building blocks for new drugs. The MX team has now validated this library in collaboration with the FragMAX group at MAX IV. The substance library of the HZB is available for research worldwide and also plays a role in the search for substances active against SARS-CoV-2.

For drugs to be effective, they usually have to dock to proteins in the organism. Like a key in a lock, part of the drug molecule must fit into recesses or cavities of the target protein. For several years now, the team of the Macromolecular Crystallography Department (MX) at HZB headed by Dr. Manfred Weiss together with the Drug Design Group headed by Prof. Gerhard Klebe (University of Marburg) has therefore been working on building up what are known as fragment libraries. These consist of small organic molecules (fragments) with which the functionally important cavities on the surface of proteins can be probed and mapped. Protein crystals are saturated with the fragments and then analysed using powerful X-ray light. This allows three-dimensional structural information to be obtained at levels of atomic resolution. Among other things, it is possible to find out how well a specific molecule fragment docks to the target protein. The development of these substance libraries took place as part of the joint Frag4Lead research project and was funded by the German Federal Ministry of Education and Research (BMBF).

Read more on the BESSY II website

Image : For the study, the enzyme endothiapepsin (grey) was combined with molecules from the fragment library. The analysis shows that numerous substances are able to dock to the enzyme (blue and orange molecules). Every substance found is a potential starting point for the development of larger molecules. 

Credit: Wollenhaupt/HZB

Formation of a 2D meta-stable oxide in reactive environments

The chemical behaviour of solid material surfaces is an important physical characteristic for applications of catalysis, chemical sensors, fuel cells and electrodes. A research team from the Max Planck Institute for Chemical Energy Conversion has now described an important phenomenon that can occur when metal alloys are exposed to reactive environments at the synchrotron source BESSY II.

In a recent work published in ACS Applied Materials & Interfaces, a researchers’ team led by Dr. Mark Greiner (Surface Structure Analysis, Department of Heterogeneous Reactions) demonstrates an important phenomenon that can occur when metal alloys face reactive environments. They can form meta-stable 2D oxides on their surfaces. Such oxides exhibit chemical and electronic properties that are different from their bulk counterparts. Due to their meta-stability, their existence is also difficult to predict.

Read more on the BESSY II (at HZB) website

Image : Illustration of a CuxOy structure formed on a AgCu alloy in oxidizing environments described in this work. (c) ACS Applied Materials & Interfaces.

Credit: © (2020) ACS Publishing

Experiment shows for the first time in detail how electrolytes become metallic

An international team has developed a sophisticated experimental technique at BESSY II to observe the formation of a metallic conduction band in electrolytes.

To accomplish this, the team first prepared cryogenic solutions of liquid ammonia containing different concentrations of alkali metals. The colour of the solutions changes with concentration from blue to golden as the individual atoms of metal in solution transition to a metallic compound. The team then examined these liquid jets using soft X-rays at BESSY II and subsequently has been able to analyse this process in detail from the data they acquired combined with theoretical predictions. The work has been published in Science and appears even on the cover.

What distinguishes metals from other materials is generally well understood. In a metal, some of the atoms’ outer electrons move through the crystalline lattice in what is called a conduction band. This is how metals conduct electric current. In contrast to metals, the ions in electrolytes are disordered and electrical conductivity even decreases with increasing ion concentration. So how does metallic behaviour arise from the many individual metal atoms dissolved in the electrolyte? At what concentration and exactly how does a conduction band form, and how do the electron orbitals behave during this process?

>Read more on the Bessy II (at HZB) website

Image: The theorists in the team have elaborately simulated the structure of the solvated electron in liquid ammonia.

Credit : Charles Universität Prag/O. Maršálek & T. Martinek

Insights into the visual perception of plants

Plants use light not only for photosynthesis. Although the plant cell does not have eyes, it can still perceive light and thus its environment. Phytochromes, certain turquoise proteins, play the central role in this process. How exactly they function is still unclear. Now a team led by plant physiologist Jon Hughes (Justus Liebig University Gießen) has been able to decipher the three-dimensional architecture of various plant phytochrome molecules at BESSY II. Their results demonstrate how light alters the structure of the phytochrome so that the cell transmits a signal to control the development of the plant accordingly.

Plants use light to live, via a process called photosynthesis. Yet, they do use light also by so called phytochromes – special molecules that give plants a kind of sight and can thus control the biochemistry of the cell and the development of the plant. It is now known that phytochromes regulate almost a quarter of the plant genome.

Read more on the BESSY II (at HZB) website

Image : Inside the 3D-structure of a phytochrome a bilin pigment absorbs the photon and rotates, which triggers a signal

Credit: Jon Hughes

How new materials increase the efficiency of direct ethanol fuel cells

A group from Brazil and an HZB team have investigated a novel composite membrane for ethanol fuel cells. It consists of the polymer Nafion, in which nanoparticles of a titanium compound are embedded by the rarely explored melt extrusion process. At BESSY II they were able to observe in detail, how the nanoparticles in the Nafion matrix are distributed and how they contribute to increase proton conductivity.

Ethanol has five times higher volumetric energy density (6.7 kWh/L) than hydrogen (1.3 kWh/L) and can be used safely in fuel cells for power generation. In Brazil in particular there is great interest in better fuel cells for ethanol as all the country distributes low-cost ethanol produced in a renewable way from sugar cane. Theoretically, the efficiency of an ethanol fuel cell should be 96 percent, but in practice at the highest power density it is only 30 percent, due to a variety of reasons. So there is great room for improvements.

Nafion with nanoparticles

A team led by Dr. Bruno Matos from the Brazilian research institute IPEN is therefore investigating novel composite membranes for direct ethanol fuel cells. A promising solution is tailoring new polymer-based composite electrolyte materials to replace the state-of-the-art polymer electrolyte such as Nafion. Matos and his team use melt extrusion process to produce composite membranes based on Nafion with additional titanate nanoparticles, which have been functionalized with sulfonic acid groups.

Read more on BESSY II (at HZB) website

Image: The material consists of Nafion with embedded nanoparticles.

Credit: © B.Matos/IPEN

New interaction between light and matter discovered at BESSY II

A German-Chinese team led by Gisela Schütz from the MPI for Intelligent Systems has discovered a new interaction between light and matter at BESSY II.

They succeeded in creating nanometer-fine magnetic vortices in a magnetic layer. These are so-called skyrmions, and candidates for future information technologies.
Skyrmions are 100 nanometre small three-dimensional structures that occur in magnetic materials. They resemble small coils: atomic elementary magnets – so-called spins – which are arranged in closed vortex structures. Skyrmions are topologically protected, i.e. their shape is unchangeable, and are therefore considered energy-efficient data storage devices.

Soft x-rays at BESSY II

In a series of experiments on the MAXYMUS beamline of BESSY II, the researchers have now shown that a bundled soft X-ray beam with a diameter of less than 50 nanometres can generate a magnetic vortex of 100 nanometres. In order to make the skyrmions visible, the researchers use the MAXYMUS scanning transmission X-ray microscope. This is a high-resolution X-ray microscope, weighing 1.8 tons, located at BESSY II.

>Read more on the BESSY II at HZB website

Image: bundled soft X-ray beam with a diameter of less than 50 nanometers writes numerous magnetic vortices, which together form the term “MPI-IS”. Credit: Alejandro Posada, Felix Groß/MPI-IS

Ultra-fast switching of helicity of circularly polarized light pulses

At the BESSY II storage ring, a joint team of accelerator physicists, undulator experts and experimenters has shown how the helicity of circularly polarized synchrotron radiation can be switched faster – up to a million times faster than before.

They used an elliptical double-undulator developed at HZB and operated the storage ring in the so-called two-orbit mode. This is a special mode of operation that was only recently developed at BESSY II and provides the basis for fast switching. The ultra-fast change of light helicity is particularly interesting to observe processes in magnetic materials and has long been expected by a large user community.
In synchrotron radiation sources such as BESSY II, electron bunches orbit the storage ring at almost the speed of light. They are forced to emit extremely bright light pulses with special properties by periodic magnetic structures (undulators).

Experiments with polarized light pulses

Elliptical undulators can be used to generate also circularly polarized light pulses, which display a feature called helicity: the polarisation goes either clockwise or counterclockwise. Magnetic structures in materials react differently to circularly polarized light: Depending on the helicity of the X-ray pulses, they more or less absorb this radiation.

>Read more on the BESSY II (HZB) website

Image: This picture shows an X-ray image of the electron beam in TRIB-mode where two orbits co-exist: the regular orbit and the second one winding around it closing only after three revolutions.
Credit: F. Armborst/K. Holldack


New detector accelerates protein crystallography

In Feburary a new detector was installed at one of the three MX beamlines at HZB.

Compared to the old detector the new one is better, faster and more sensitive. It allows to acquire complete data sets of complex proteins within a very short time.

Proteins consist of thousands of building blocks that can form complex architectures with folded or entangled regions. However, their shape plays a decisive role in the function of the protein in the organism. Using macromolecular crystallography at BESSY II, it is possible to decipher the architecture of protein molecules. For this purpose, tiny protein crystals are irradiated with X-ray light from the synchrotron source BESSY II. From the obtained diffraction patterns, the morphology of the molecules can be calculated.

>Read more on the BESSY II at HZB website

Image: 60s on the new detector were sufficient to obtain the electron density of the PETase enzyme.
Credit: HZB

X-ray microscopy at BESSY II: Nanoparticles can change cells

Nanoparticles easily enter into cells. New insights about how they are distributed and what they do there are shown for the first time by high-resolution 3D microscopy images from BESSY II.

For example, certain nanoparticles accumulate preferentially in certain organelles of the cell. This can increase the energy costs in the cell. “The cell looks like it has just run a marathon, apparently, the cell requires energy to absorb such nanoparticles” says lead author James McNally.
Today, nanoparticles are not only in cosmetic products, but everywhere, in the air, in water, in the soil and in food. Because they are so tiny, they easily enter into the cells in our body. This is also of interest for medical applications: Nanoparticles coated with active ingredients could be specifically introduced into cells, for example to destroy cancer cells. However, there is still much to be learned about how nanoparticles are distributed in the cells, what they do there, and how these effects depend on their size and coating.

>Read more on the BESSY II at Helmholtz-Zentrum Berlin website

Image: 3D architecture of the cell with different organelles:  mitochondria (green), lysosomes (purple), multivesicular bodies (red), endoplasmic reticulum (cream).
Credit: Burcu Kepsutlu/HZB

Watching complex molecules at work

A new method of infrared spectroscopy developed at BESSY II makes single-measurement observation and analysis of very fast as well as irreversible reaction mechanisms in molecules feasible for the first time.

Previously, thousands of such reactions have had to be run and measured for this purpose. The research team has now used the new device to investigate how rhodopsin molecules change after activation by light – a process that is the basis of how we see.

Time-resolved infrared spectroscopy in the sub-millisecond range is an important method for studying the relationship between function and structure in biological molecules. However, the method only works if the reaction can be repeated many thousands of times. This is not the case for a large number of biological processes, though, because they often are based on very rapid and irreversible reactions, for example in vision. Individual light quanta entering the rods of the retina activate the rhodopsin protein molecules, which then decay after fulfilling their phototransductionfunction.

>Read more on the BESSY II at HZB website

Image: Rhodopsin before (left) and after activation by light (right): The activation causes changes in functional groups inside the molecule (magnifying glass), which affect the entire molecule.
Credit: E. Ritter/HZB

The mechanism of the most commonly used antimalarial drugs unveiled

For centuries, quinoline has been an effective compound in antimalarial drugs, although no one knew its mode of action in vivo.

Today, a team led by the Weizmann Institute has discovered its mechanism in infected red blood cells in near-native conditions, by using the ESRF, Alba Synchrotron and BESSY. They publish their results in PNAS.

Malaria remains one of the biggest killers in low-income countries. Estimates of the number of deaths each year range from 450,000 to 720,000, with the majority of deaths happening in Africa. In the last two decades, the malaria parasite has evolved into drug-resistant strains. “Recently, the increasing geographical spread of the species, as well as resistant strains has concerned the scientific community, and in order to improve antimalarial drugs we need to know how they work precisely”, explains Sergey Kapishnikov, from the University of Copenhagen, in Denmark, and the Weizmann Institute, in Israel, and leader of the study.

Plasmodium parasite, when infecting a human, invades a red blood cell, where it ingests hemoglobin to grow and multiply. Hemoglobin releases then iron-containing heme molecules, which are toxic to the parasite. However, these molecules crystallise into hemozoin, a disposal product formed from the digestion of blood by the parasite that makes the molecules inert. For the parasite to survive, the rate at which the heme molecules are liberated must be slower or the same as the rate of hemozoin crystallization. Otherwise there would be an accumulation of the toxic heme within the parasite.

>Read more on the ESRF website

Image (taken from BESSY II article): The image shows details such as the vacuole of the parasites (colored in blue and green) inside an infected blood cell.
Credit:
S. Kapishnikov

Two other institutes, BESSY II at HZB and ALBA Synchrotron, have participated in this research. Please find here their published articles:

> X-ray microscopy at BESSY II reveal how antimalaria-drugs might work

> The mechanism of the most commonly used antimlalarial drugs in near- native conditions unveiled

Dynamic pattern of skyrmions observed

Tiny magnetic vortices known as skyrmions form in certain magnetic materials, such as Cu2OSeO3.

These skyrmions can be controlled by low-level electrical currents – which could facilitate more energy-efficient data processing. Now a team has succeeded in developing a new technique at the VEKMAG station of BESSY II for precisely measuring these vortices and observing their three different predicted characteristic oscillation modes (Eigen modes).

Cu2OSeO3 is a material with unusual magnetic properties. Magnetic spin vortices known as skyrmions are formed within a certain temperature range when in the presence of a small external magnetic field. Currently, moderately low temperatures of around 60 Kelvin (-213 degrees Celsius) are required to stabilise their phase, but it appears possible to shift this temperature range to room temperature. The exciting thing about skyrmions is that they can be set in motion and controlled very easily, thus offering new opportunities to reduce the energy required for data processing.

>Read more on the BESSY II at HZB website

Image: The illustration demonstrates skyrmions in one of their Eigen modes (clockwise).
Credit: Yotta Kippe/HZB

New sample holder for protein crystallography

An HZB research team has developed a novel sample holder that considerably facilitates the preparation of protein crystals for structural analysis.

A short video by the team shows how proteins in solution can be crystallised directly onto the new sample holders themselves, then analysed using the MX beamlines at BESSY II. A patent has already been granted and a manufacturer found. Proteins are huge molecules that often have complex three-dimensional structure and morphology that can include side chains, folds, and twists. This three-dimensional shape is often the determining factor of their function in organisms. It is therefore important to understand the structure of proteins both for fundamental research in biology and for the development of new drugs. To accomplish this, proteins are first precipitated from solution as tiny crystals, then analysed using facilities such as the MX beamlines at BESSY II in order to generate a computer image of the macromolecular structure from the data.

>Read more on the BESSY II at HZB website

Image: Up to three indivudal drops may be placed onto the sample holder.
Credit: HZB

World record in tomography: watching how metal foam forms

An international research team at the Swiss Light Source (SLS) has set a new tomography world record using a rotary sample table developed at the HZB.

With 208 three-dimensional tomographic X-ray images per second, they were able to document the dynamic processes involved in the foaming of liquid aluminium. The method is presented in the journal Nature Communications.
The precision rotary sample table designed at the HZB rotates around its axis at several hundred revolutions per second with extreme precision. The HZB team headed Dr. Francisco García-Moreno combined the rotary sample table with high-resolution optics and achieved a world record of over 25 tomographic images per second using the BESSY II EDDI beamline in 2018.

>Read more on the Bessy II at HZB wesbite

Image: The precision rotary sample table designed at the HZB turns around its axis at several hundred revolutions per second with extreme precision.
Credit: © HZB

“Invisible ink” on antique Nile papyrus revealed by multiple methods

Researchers from the Egyptian Museum and Papyrus Collection, Berlin universities and Helmholtz-Zentrum Berlin studied a small piece of papyrus that was excavated on the island of Elephantine on the River Nile a little over 100 years ago.

The team used serval methods including non-destructive techniques at BESSY II. The researchers’ work, reported in the Journal of Cultural Heritage, blazes a trail for further analyses of the papyrus collection in Berlin.

The first thing that catches an archaeologist’s eye on the small piece of papyrus from Elephantine Island on the Nile is the apparently blank patch. Researchers from the Egyptian Museum, Berlin universities and Helmholtz-Zentrum Berlin have now used the synchrotron radiation from BESSY II to unveil its secret. This pushes the door wide open for analysing the giant Berlin papyrus collection and many more.

>Read more on the BESSY II at HZB website

Illustration: A team of researchers examined an ancient papyrus with a supposed empty spot. With the help of several methods, they discovered which signs once stood in this place and which ink was used.
Credit: © HZB

Alternative material investigated for superconducting radio-frequency cavity resonators

In modern synchrotron sources and free-electron lasers, superconducting radio-frequency cavity resonators are able to supply electron bunches with extremely high energy. These resonators are currently constructed of pure niobium. Now an international collaboration has investigated the potential advantages a niobium-tin coating might offer in comparison to pure niobium.
At present, niobium is the material of choice for constructing superconducting radio-frequency cavity resonators. These will be used in projects at the HZBsuch as bERLinPro and BESSY-VSR, but also for free-electron lasers such as the XFEL and LCLS-II. However, a coating of niobium-tin (Nb3Sn) could lead to considerable improvements.

Coatings may save money and energy

Superconducting radio-frequency cavity resonators made of niobium must be operated at 2 Kelvin (-271 degrees Celsius), which requires expensive and complicated cryogenic engineering. In contrast, a coating of Nb3Sn might make it possible to operate resonators at 4 Kelvin instead of 2 Kelvin and possibly withstand higher electromagnetic fields without the superconductivity collapsing. In the future, this could save millions of euros in construction and electricity costs for large accelerators, as the cost of cooling would be substantially lower.

> Read more on the HZB website

Image: The photomontage shows a sample of solid, pure niobium before coating (left), and coated with a thin layer of Nb3Sn (right). Copyright: HZB