Category: Chemistry

On average, we open seven packaged items per day, most of them food items. All of this together makes for a mountain of plastic. But more and more often our tomatoes, apples and cookies are packaged in cardboard. To help speed up the transition of plastic to paper, TU/e chemist Sterre Bakker researched what coatings can be used to make cardboard a more suitable food packaging material.

About 20% of waste consists of packaging, but packaging food is not all bad. Good packaging protects the item during transport, which means less food needs to be thrown out. Packaging also keeps out moisture, bacteria and fungi. This gives our food a longer shelf life, also resulting in less food going to waste. Keeping a bag of mixed vegetables or a pack of beef in the fridge for a week without it going off? Impossible without the packaging.

More alternatives are being used to reduce plastic packaging waste. Over the past few years, paper and cardboard have become more common packaging materials. But transitioning from plastic to paper is not as easy as it seems, TU/e researcher Sterre Bakker explains. “Plastic has a number of highly practical characteristics. You can use it for airtight packaging and it is an excellent barrier for water and grease. It’s strong but also light, which works well for the transport sector. It requires a lot of effort to find a suitable alternative that meets the same requirements and can be used at a large scale.”

Freedom to publish

For her Ph.D., Bakker investigated how cardboard can be used to make food packaging more sustainable. This Friday (Jan. 27, 2023) she will defend her thesis at the department of Chemical Engineering and Chemistry. To bridge the gap between the laboratory and the packaging sector, she collaborated with chemicals company BASF.

When asked if this collaboration caused any confidentiality issues, Bakker shakes her head. “I consciously sought collaboration with industry; I wanted to get a PHD, but in applied research. This allowed me to make a contribution to society. As I wanted to have the freedom to talk and publish about my findings, we used a model coating. It’s not exactly the same as the manufacturer’s, but it’s very similar. So that was a good compromise.”

Water-based coating

For dry food items, such as rice and oatmeal, cardboard packaging works fine. But putting milk or a hamburger in a cardboard box is more complex, Bakker explains. “A suitable coating is crucial. Water and grease have very different ways of getting through a coating. For a good water barrier, the chemical reaction that occurs while the coating is drying up is very important, but for grease you need a coating that’s intact. This explains why the inner lining of a milk carton is so thick: it consists of several layers of hydrophilic and hydrophobic coatings. In addition to the relatively large amount of plastic used, the mixture of coatings makes it hard to recycle. This is what we would like to improve.”

Bakker set out in search of a single coating impermeant to water, oxygen and grease. To this end, she studied an innovative, water-based coating, with the special addition of a water-soluble, synthetic resin to stabilize polymer particles. This resin makes it possible to transform a water-soluble surface into a water-resistant one. “When the coating dries up, it’s not only the water that evaporates but also a base. The resin undergoes a chemical reaction and this means the coating no longer dissolves in water.”

Multifunctional coating

Bakker used a scanning electron microscope and infrared spectroscopy to carry out in-depth research into the different barrier characteristics of the coating, as well as to optimize the production process. This is all very relevant to industry, she emphasizes, as synthesizing the coating is easy to scale and not overly complex. What’s more, at a certain temperature the color of the coating can be changed by adding a specific molecule. This quasi-alternative expiration date makes the coating multifunctional.

Bakker shows her final result: a shiny piece of thick carton that actually resists both water and grease. “This coating already has a lot of advantages in comparison to current coatings. Although it does require raw fossil materials, the layer can be made much thinner now. We’ve also demonstrated through several experiments that the coating can be peeled off the cardboard more easily, which means it’s very suitable for recycling. We’ve taken the first steps, obviously in the hope of eventually creating a biobased coating that eliminates all plastic from food packaging.”

Tea lover

The above should serve as a reminder, Bakker reiterates, of cardboard being much stronger than we give it credit for. Like women, she says with a smile. Bakker is quite comfortable in the space she created for herself in the male-dominated coating and packaging industry. And as a tea lover she will obviously bring her tea box—cardboard of course—to her new place of work, Allnex in Bergen op Zoom. Before we leave she’s keen to show us the quote adorning her thesis: “A woman is like a teabag; you never know how strong it is until it is in hot water.”

Sterre Bakker defends her thesis at the department of Chemical Engineering and Chemistry on January 27, 2023.

Provided by Eindhoven University of Technology 

The dairy industry strives to preserve the quality and safety of milk products while maintaining the freshest possible taste for consumers. To date, the industry has largely focused on packaging milk in light-blocking containers to preserve freshness, but little has been understood about how the packaging itself influences milk flavor. However, a new study in the Journal of Dairy Science confirms that packaging affects taste—and paperboard cartons do not preserve milk freshness as well as glass and plastic containers.

Lead investigator MaryAnne Drake, Ph.D., of the North Carolina State University Department of Food, Bioprocessing and Nutrition Sciences, Raleigh, NC, U.S., explained that “milk is more susceptible to packaging-related off-flavors than many other beverages because of its mild, delicate taste.” Besides light oxidation, “milk’s taste can be impacted by the exchange of the packaging’s compounds into the milk and by the packaging absorbing food flavors and aromas from the surrounding refrigeration environment.”

To quantify the flavor impacts of packaging, the researchers examined pasteurized whole and skim milk stored in six half pint containers: paperboard cartons, three plastic jugs (made from different plastics), a plastic bag, and glass as a control. The milk was stored in total darkness to control for light oxidation and kept cold at 4°C (39°F).

The samples were tested on the day of first processing, then again at 5, 10, and 15 days after. A trained panel examined the sensory properties of each sample, and the research team conducted a volatile compound analysis to understand how the packaging was intermingling with the milk. Finally, the samples underwent a blind consumer taste test on day 10 to see whether tasters could tell any difference between milk stored in the paperboard carton or the plastic jug compared with milk packaged in glass.

The results showed that package type does influence milk flavor, and skim milk is more susceptible to flavor impacts than whole milk. Of the different packaging types, paperboard cartons and the plastic bag preserved milk freshness the least due to the paperboard’s absorption of milk flavor and the transfer of paperboard flavor into the milk. Milk packaged in paperboard cartons, in fact, showed distinct off-flavors as well as the presence of compounds from the paperboard. The final results show that while glass remains an ideal container for preserving milk flavor, plastic containers provide additional benefits while also maintaining freshness in the absence of light exposure.

Paperboard cartons are the most widely used packaging type for school meal programs in the United States, so these findings are especially relevant for the consideration of how young children consume and enjoy milk.

“These findings suggest that industry and policymakers might want to consider seeking new package alternatives for milk served during school meals,” said Drake. Over time, the consequences of using milk packaging that contributes significant off-flavors may affect how young children perceive milk in both childhood and adulthood.

More information: D.C. Cadwallader et al, The role of packaging on the flavor of fluid milk, Journal of Dairy Science (2022). DOI: 10.3168/jds.2022-22060

Journal information: Journal of Dairy Science 

Provided by Elsevier 

Researchers from Skoltech and Tomsk Polytechnic University have tuned the synthesis of a five-element carbide—a strong, hard-melting compound of carbon and five transition metals—which holds much promise for industrial ceramics and catalysis.

The team relied on fundamental theoretical principles, simulations, and machine learning to identify conditions for the synthesis of single-phase carbide, in which all metal atoms are evenly distributed throughout the crystal. The predictions were confirmed by an experiment using the advanced energy-efficient vacuumless electric arc synthesis method. The study is published in npj Computational Materials.

High-entropy carbides (HECs) are multicomponent equimolar single-phase solid solutions of five or more metals from groups four and five of the periodic table with a cubic NaCl-type crystal structure. One of the key factors of HEC stabilization is configurational, or mixing, entropy, which should be higher than 1.5 times the universal gas constant. This means that the compound should contain at least five basic elements.

HECs attract increasing attention from researchers owing to their unique mechanical properties, a high melting point, and low thermal conductivity. Also, they boast greater hardness, fracture toughness, and temperature stability than individual metal carbides.

The most common HEC synthesis method is reactive spark plasma sintering (SPS) of pre-homogenized raw materials based on individual metal carbides, pure metals, or metal oxides. Typically, HECs are synthesized at high temperatures of about 2,200-2,300 degrees Celsius, and SPS is applied at pressures of about 10–60 MPa with a dwell of 10–15 minutes, whereas homogenization of raw materials can take more than one day.

“The vacuumless electric arc synthesis method helps to produce powdered HECs without using complex, expensive and energy-consuming equipment, such as vacuum pumps for high vacuum or compressors for external pressure. Our set-up is unique in that it does not need pressure or vacuum to produce HECs,” Alexander Pak, the head of the Advanced Energy Materials Laboratory and manager of the Energy of the Future strategic project at TPU, explains.

“Moreover, we can obtain both multi-phase and single-phase carbides by flexibly varying synthesis parameters. HECs are a fairly new class of materials, so we have yet to identify their actual properties and potential uses, which will likely include refractory ceramics and various types of catalysts.”

The team used the Canonical Monte Carlo (CMC) simulation with machine learning interatomic potentials and performed first-principles calculations to determine synthesis temperatures for single- and multiphase carbides. According to the calculations, low-temperature synthesis will produce mostly multiphase HECs with two or more coexisting phases of multicomponent carbides, while synthesis at above 1,500 C will result in single-phase HECs.

“By applying the CMC method, we have succeeded in predicting the HEC’s thermodynamically stable crystal structure at different synthesis temperatures and, as a result, finding the multi-to-single phase transition temperature. Our experiments at temperatures below and above the transition point confirmed the simulation results. Thus, we were able to implement a complete research sequence, going all the way from a computer model to a physical sample,” Skoltech Ph.D. student Vadim Sotskov from the AI for materials science group notes.

More information: Alexander Ya. Pak et al, Machine learning-driven synthesis of TiZrNbHfTaC₅ high-entropy carbide, npj Computational Materials (2023). DOI: 10.1038/s41524-022-00955-9

Provided by Skolkovo Institute of Science and Technology 

New research has uncovered the secret of how plants make limonoids, a family of valuable organic chemicals that include bee-friendly insecticides and have potential as anti-cancer drugs.

The research team, a collaboration between the John Innes Centre and Stanford University, used groundbreaking methods to reveal the biosynthetic pathway of these useful molecules, which are made by certain plant families, including mahogany and citrus.

In the study, which appears in Science, the John Innes Centre research team used genomic tools to map the genome of Chinaberry (Melia azedarach), a mahogany species, and combined this with molecular analysis to reveal the enzymes in the biosynthetic pathway.

“By finding the enzymes required to make limonoids, we have opened the door to an alternate production source of these valuable chemicals,” explained Dr. Hannah Hodgson, co-first author of the paper and a postdoctoral scientist at the John Innes Centre.

Until now, limonoids, a type of triterpene, could only be produced by extraction from plant material.

Dr. Hodgson explained, “Their structures are too complicated to efficiently make by chemical synthesis. With the knowledge of the biosynthetic pathway, it is now possible to use a host organism to produce these compounds.” she added.

Armed with the complete biosynthetic pathway researchers can now produce the chemicals in commonly used host plants such as Nicotiana benthamiana. This method can produce larger quantities of limonoids in a more sustainable way.

Increasing the supply of limonoids could enable the more widespread use of azadirachtin, the anti-insect limonoid obtained from the neem tree and used in commercial and traditional crop protection. Azadirachtin is an effective, fast degrading, bee-friendly option for crop protection but is not widely used due to limited supply.

The team made two relatively simple limonoids, azadirone from Chinaberry, and kihadalactone A from citrus, and believe that the methods used here can now be applied as a template for making more complicated triterpenes.

The team at John Innes used genomic tools to assemble a chromosome level genome for Chinaberry (Melia azedarach), within which they found the genes encoding 10 additional enzymes required to produce the azadirachtin precursor, azadirone. In parallel, the team working at Stanford were able to find the 12 additional enzymes required to make khidalactone A.

Expressing these enzymes in N. benthamiana enabled their characterization, with the help of both Liquid chromatography–mass spectrometry (LC-MS) and Nuclear Magnetic Resonance (NMR) Spectroscopy, technologies that allow molecular level analysis of samples.

Professor Anne Osbourn, group leader at the John Innes Centre and co-corresponding author of the study, said, “Plants make a wide variety of specialized metabolites that can be useful to humans. We are only just starting to understand how plants make complex chemicals like limonoids. Prior to this project, their biosynthesis and the enzymes involved were completely unknown; now the door is open for future research to build on this knowledge, which could benefit people in many ways.”

Another example of a high value limonoid that the team hopes to produce is the anti-cancer drug candidate nimbolide; this work could enable easier access to limonoids like nimbolide to enable further study. As well as producing known products like nimbolide, the research team says the door may open to understanding new activities for limonoids that have not yet been investigated.

More information: Ricardo De La Peña et al, Complex scaffold remodeling in plant triterpene biosynthesis, Science (2023). DOI: 10.1126/science.adf1017. www.science.org/doi/10.1126/science.adf1017

Journal information: Science 

Provided by John Innes Centre 

Smart materials are materials that have the ability to change their properties in response to specific external stimuli, such as temperature, humidity, light, or applied stress. One of the most well-known examples of smart materials is shape memory alloy (SMA), which is a type of metallic material that can change its shape in response to changes in temperature.

Another example of smart materials includes piezoelectric materials, which generate an electric charge in response to applied mechanical stress. Smart materials have a wide range of potential applications, including in aerospace, automotive, robotics, manufacturing, and biomedical engineering.

Variable stiffness materials are a type of smart materials that have the ability to tune their stiffness, or resistance to deformation, in response to external stimuli. This property allows for the material to adapt to changing conditions and improve performance in a wide range of environments.

One of the main advantages of variable stiffness materials is that they can increase the efficiency, safety, and reliability of mechanical systems. For example, variable stiffness materials can be used to create robotic arms and grippers that can adapt to different objects and environments. This allows for the robotic arm or gripper to handle a range of different objects with different shapes, sizes, and weights, which can reduce the complexity and increase the overall efficiency of the robotic system.

Innovative smart materials with tuneable electromechanical properties are revolutionizing the fields of manufacturing, wearable devices, and robotics. However, to date, a material that can intelligently self-tune its electrical and mechanical properties in response to environmental changes, and harness the altered properties synergistically without external control, has yet to be achieved.

To fill this gap, a collaborative research team led by Dr. Shiyang Tang at the University of Birmingham, along with collaborators from the University of Science and Technology of China, the University of Cambridge, and the University of Wollongong, developed a smart material called the Field’s metal hybrid filler elastomer (FMHE). The FMHE comprises hybrid fillers of Field’s metal (a non-toxic low-melting-point alloy) and spiked nickel microparticles embedded in an elastomer matrix.

This research was reported in their recent paper published in Science Advances.

The FMHE created by the researchers can respond to both mechanical strain and electrical currents, exhibiting variable and tuneable electrical conductivity and stiffness without external control. The melting and solidification of the Field’s metal enable the change in stiffness. The FMHE also exhibits unconventional negative piezoresistivity and high strain sensitivity, with resistivity decreasing millions of times upon both compression and stretching.

By harnessing these properties in a synergistic manner, the researchers demonstrated two applications in intelligent and resilient systems, with over an order of magnitude performance improvement compared to the state-of-the-art. The first application is a self-triggered multi-axis compliance compensator that can protect robotic manipulators from excessive compressive, bending, and torsional movements.

The second application is a resettable current-limiting fuse that offers adjustable fusing currents and significantly outperforms commercial products in terms of compactness, range of operating current, and response speed.

“I am thrilled that our experiments and simulations have uncovered the mechanism behind the negative piezoresistive effect and the tuneable conductivity, strain sensitivity, and stiffness of this smart material. I hope this research is the beginning of the further study on this new material family, which has the potential to revolutionize the development of intelligent and resilient robotics and electronics,” said Dr. Guolin Yun, the first author of the study.

“These self-responsive smart materials not only offer cost-saving opportunities but also increase reliability by reducing the need for complex control systems,” said Dr. Shiyang Tang.

This study provides significant value to the fields of manufacturing, robotics, and electronics, potentially leading to the development of electromechanical systems with enhanced performance and functionality.

More information: Guolin Yun et al, Electro-mechano responsive elastomers with self-tunable conductivity and stiffness, Science Advances (2023). DOI: 10.1126/sciadv.adf1141

Journal information: Science Advances 

Provided by University of Birmingham 

A study published in ACS Applied Materials & Interfaces describes a novel method of producing hydrogen peroxide (H₂O₂) without emitting carbon dioxide (CO₂), one of the main greenhouse gases and one of the world’s most widely produced chemicals.

Hydrogen peroxide is used to bleach fabric, pulp and paper, and to whiten teeth. It is also used as a thruster fuel for satellite attitude control, and as a disinfectant or sterilizing agent by hospitals. Some 2 million metric tons of the compound are produced annually.

“To understand the impact of our findings, it’s important first and foremost to bear in mind the significance of H₂O₂ in the chemical industry and the way it’s currently produced,” said Ivo Freitas Teixeira, a professor of chemistry at the Federal University of São Carlos (UFSCar) in São Paulo State, Brazil. He has a Ph.D. in inorganic chemistry from the University of São Paulo (USP) and was a Humboldt Fellow at the Max Planck Institute of Colloids and Interfaces in Potsdam, Germany, between 2019 and 2021.

“All this peroxide is produced by a process that involves anthraquinone [a compound derived from hydrolysis of anthracene, a toxic substance]. In this process, anthraquinone is reduced and then oxidized to make H₂O₂. The drawbacks of the method are the high cost of anthraquinone and the use of precious metals such as Pd [palladium], and H₂ [hydrogen] as reducing agents. This hydrogen is produced by steam-methane reforming, which involves high temperatures and releases CO₂, contributing to global warming,” he said.

In the study, the researchers produced peroxide from oxygen (O₂) using photocatalysis to guide the process. In photocatalysis, the catalysts (substances that accelerate the chemical reaction) are activated by visible light instead of high temperature or pressure. Another advantage of their method was the use of carbon nitride as a photocatalyst.

This material consists only of carbon and nitrogen, both of which are abundant in Earth’s crust, and can be activated in the visible region, which corresponds to about 45% of the solar spectrum. It is therefore probable that sunlight can be used instead of artificial lighting, making the process more cost-effective.

After testing different reaction conditions, the researchers arrived at a system with an excellent rate of H₂O₂ production. “We achieved O₂ reduction via a photocatalytic route in which the hydrogen source was the water in the reaction medium or the sacrificial reagent, typically glycerol, a byproduct of biodiesel production,” Teixeira explained.

In this system, carbon nitride is used as a semiconductor to separate charges when bathed in light, promoting reduction and oxidation reactions. The O₂ is reduced to H₂O₂ and the sacrificial reagent (glycerol) is oxidized. The H₂O₂ is obtained without the need to use H₂ and hence without CO₂ emissions.

“The road we had to travel in our investigation until we arrived at the results described in the published article was a long one because we discovered that at the same time as H₂O₂ was produced on the surface of the photocatalyst, it could also be degraded,” Teixeira said.

“We had to perform several tests and keep modifying the photocatalyst in order to promote the formation of H₂O₂ and avoid its decomposition. Understanding the mechanism whereby H₂O ₂ decomposes on the surface of carbon nitride was extremely important to enable us to develop the ideal photocatalyst for this reaction.”

More information: Andrea Rogolino et al, Modified Poly(Heptazine Imides): Minimizing H₂O₂ Decomposition to Maximize Oxygen Reduction, ACS Applied Materials & Interfaces (2022). DOI: 10.1021/acsami.2c14872

Journal information: ACS Applied Materials and Interfaces 

Provided by FAPESP 

Investigating the interplay between the structure of water molecules that have been incorporated into layered materials such as clays and the configuration of ions in such materials has long proved a great experimental challenge. But researchers have now used a technique elsewhere commonly used to measure extremely tiny masses and molecular interactions at the nano level to observe these interactions for the first time.

Their research was published in Nature Communications.

Many materials take a layered form at the microscopic or nano-scale. When dry, clays resemble a series of sheets stacked upon each other. When such layered materials encounter water, however, that water can be confined and integrated into the gaps or holes—or, more accurately, the pores—between layers.

Such ‘hydration’ can also occur when water molecules or their constituent elements, notably a hydroxide ion (a negatively charged ion combining a single oxygen and single hydrogen atom) are integrated into the crystalline structure of the material. This type of material, a hydrate, is not necessarily “wet” even though water is now part of it. Hydration can also substantially change the original material’s structure and properties.

In this nanoconfinement, the hydration structures—how water molecules or their constituent elements arrange themselves—determine the ability of the original material to store ions (positively or negatively charged atoms or groups of atoms).

This storage of water or charge means that such layered materials, from conventional clays to layered metal oxides—and, crucially, their interactions with water—have widespread applications, from water purification to energy storage.

However, studying the interplay between this hydration structure and the configuration of ions in the ion storage mechanism of such layered materials has proven to be a great challenge. And efforts at analyzing how these hydration structures change over the course of any movement of these ions (‘ion transport’) are even more difficult.

Recent research has shown that such water structures and interactions with the layered materials play an important role in giving the latter their high ion-storage capacities, all of which in turn depends upon how flexible the layers that host the water are. In the space between layers, any pores that are not filled with ions get filled with water molecules instead, helping to stabilize the layered structure.

“Put another way, the water structures are sensitive to how the interlayer ions are structured,” said Katsuya Teshima, corresponding author of the study and a materials chemist with the Research Initiative for Supra-Materials at Shinshu University. “And while this ion configuration in many different crystal structures controls how many ions can be stored, such configurations until now had rarely been systematically investigated.”

So Teshima’s group looked to quartz crystal microbalance with energy dissipation monitoring (QCM-D) to assist with their theoretical calculations. QCM-D is essentially an instrument that works like a balance scale that can measure extremely tiny masses and molecular interactions at the nano level. The technique can also measure tiny changes in energy loss.

The researchers used QCM-D to demonstrate for the first time that the change in the structure of water molecules confined in the nano-space of layered materials can be experimentally observed.

They did this by measuring the “hardness” of the materials. They investigated the layered double hydroxides (LDHs) of a class of negatively charged clay. They found that the hydration structures were associated with the hardening of the LDHs when any ion exchange reaction happens (a swapping of one kind of ion with a different type of ion but with the same change).

“In other words, any change in ion interaction originates with the change in the hydration structure that occurs when ions are incorporated into the nano-space,” added Tomohito Sudare, a collaborator on the study now with the University of Tokyo.

In addition, the researchers found that the hydration structure is highly dependent on the charge density (the amount of charge per unit of volume) of the layered material. This in turn is largely what governs the ion storage capacity.

The researchers now hope to apply these measurement methods together with the knowledge of the hydration structure of ions to devise new techniques for improving the ion-storage capability of layered materials, potentially opening new avenues for ion separation and sustainable energy storage.

More information: Tomohito Sudare et al, Critical role of water structure around interlayer ions for ion storage in layered double hydroxides, Nature Communications (2022). DOI: 10.1038/s41467-022-34124-9

Journal information: Nature Communications 

Provided by Shinshu University

Developing new antifungal treatments is a rising health priority due to an alarming rise in multidrug-resistant fungal “superbugs” that evade medications clinicians have relied on for decades.

Now, a Texas A&M University System team’s work is launching the next steps toward the discovery of new antifungal medications.

Drug-resistant fungal species affect at least 3.6 million people annually in the U.S. alone, with a direct medical cost of $3 billion. Fungal infections can progress to severe illness or death, and the window for effective treatment is short. Hospital patients with suppressed immune systems are particularly vulnerable to these pathogens.

However, fungal cells share many similarities with human cells, so treatments effective against fungi can have undesired toxic effects on human cells. Newly developed drugs must efficiently limit fungal survivability without causing additional complications in patients.

Therefore, identifying both the right targets in fungi and the small molecule inhibitors that restrain those target activities with exquisite sensitivity are necessary first steps in antifungal drug discovery.

Both these first steps were achieved in a study recently published in the Journal of Biological Chemistry. The study’s senior authors are Tatyana Igumenova, Ph.D., associate professor in the Department of Biochemistry and Biophysics at the Texas A&M College of Agriculture and Life Sciences, and Vytas Bankaitis, Ph.D., the E.L. Wehner-Welch Chair in the Department of Cell Biology and Genetics at the Texas A&M University School of Medicine. Xiao-Ru Chen, the lead author of the work, is a graduate student in the Department of Biochemistry and Biophysics.

Specifically, the research team uncovered how diverse small molecules inhibit an essential regulator of a fungal signaling molecule called Sec14. Sec14 is a protein that executes membrane trafficking functions that fungal cells need to grow and form biofilms. It is also essential for fungal survival and disease development in pathogenic fungi.

An example of basic and translational research

The Journal of Biological Chemistry highlighted this study as a “Recommended Read”—a designation it reserves for papers of especially high quality.

“This study is an excellent example of the tight linkage between basic science and the development of new directions of translational science,” Bankaitis said.

“From the basic science perspective, the small molecule inhibitors are proving to be enormously useful as tool compounds by which we can dissect how Sec14 functions as a signaling regulator. This problem is of intense interest as Sec14 and other members of the Sec14 protein family are functionally mysterious from a biochemical and biophysical point of view. Yet that very same body of information translates directly to developing rational strategies for producing next-generation antifungal drugs.”

Toward the next steps in antifungal drug discovery

Using baker’s yeast as a model fungus, team members identified four new classes of antifungal molecules that inhibit Sec14 proteins in yeast and in some virulent fungi. These small molecule inhibitors, or SMIs, compete with native fungal ligands that Sec14 depends on to execute signaling functions. When these new inhibitors bind to Sec14, they interfere with fungal virulence.

“The application of cutting-edge integrative structural biology approaches was essential to decipher the mechanisms by which Sec14 was inhibited by each SMI,” Igumenova said.

“It required the use of X-ray crystallography, molecular dynamics simulations and high-resolution nuclear magnetic resonance spectroscopy to obtain an atomistic description of how Sec14 interacts with SMIs and the principles behind the exquisite Sec14 binding specificity. Of particular note is our innovative use of fluorine nuclear magnetic resonance spectroscopy to directly monitor the competition between native fungal ligands and SMIs.”

The team’s discovery of how SMIs bind to Sec14 now launches the next steps in drug discovery. This research validates a new target and details new strategies for rational structure-based development of next-generation antifungal drugs.

More information: Xiao-Ru Chen et al, Mechanisms by Which Small Molecules of Diverse Chemotypes Arrest Sec14 Lipid Transfer Activity, Journal of Biological Chemistry (2023). DOI: 10.1016/j.jbc.2022.102861

Journal information: Journal of Biological Chemistry 

Provided by Texas A&M University 

According to the World Health Organization, each year there are an estimated 1 billion cases of influenza, between 3-5 million severe cases and up to 650,000 influenza-related respiratory deaths globally. Seasonal flu vaccines must be reformulated each year to match the predominantly circulating strains. When the vaccine matches the predominant strain, it is very effective; however, when it does not match, it may offer little protection.

The main targets of the flu vaccine are two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). While the HA protein helps the virus bind to the host cell, the NA protein acts like scissors to cut the HA away from the cell membrane allowing the virus to replicate. Although the properties of both glycoproteins have been studied previously, a complete understanding of their movement does not exist.

For the first time, researchers at the University of California San Diego have created an atomic-level computer model of the H1N1 virus that reveals new vulnerabilities through glycoprotein “breathing” and “tilting” movements. This work, published in ACS Central Science, suggests possible strategies for the design of future vaccines and antivirals against influenza.

“When we first saw how dynamic these glycoproteins were, the large degree of breathing and tilting, we actually wondered if there was something wrong with our simulations,” stated Distinguished Professor of Chemistry and Biochemistry Rommie Amaro, who is the principal investigator on the project. “Once we knew our models were correct, we realized the enormous potential this discovery held. This research could be used to develop methods of keeping the protein locked open so that it would be constantly accessible to antibodies.”

Traditionally, flu vaccines have targeted the head of the HA protein based on still images that showed the protein in a tight formation with little movement. Amaro’s model showed the dynamic nature of the HA protein and revealed a breathing movement that exposed a previously unknown site of immune response, known as an epitope.

This discovery complemented previous work from one of the paper’s co-authors, Ian A. Wilson, Hansen Professor of Structural Biology at The Scripps Research Institute, who had discovered an antibody that was broadly neutralizing—in other words, not strain-specific—and bound to a part of the protein that appeared unexposed. This suggested that the glycoproteins were more dynamic than previously thought, allowing the antibody an opportunity to attach. Simulating the breathing movement of the HA protein established a connection.

NA proteins also showed movement at the atomic level with a head-tilting movement. This provided a key insight to co-authors Julia Lederhofer and Masaru Kanekiyo at the National Institute of Allergy and Infectious Diseases. When they looked at convalescent plasma—that is, plasma from patients recovering from the flu—they found antibodies specifically targeting what is called the “dark side” of NA underneath the head.

Without seeing the movement of NA proteins, it wasn’t clear how the antibodies were accessing the epitope. The simulations Amaro’s lab created showed an incredible range of motion that gave insight into how the epitope was exposed for antibody binding.

The H1N1 simulation Amaro’s team created contains an enormous amount of detail—160 million atoms worth. A simulation of this size and complexity can only run on a few select machines in the world. For this work, the Amaro lab used Titan at Oak Ridge National Lab, formerly one of the largest and fastest computers in the world.

Amaro is making the data available to other researchers who can uncover even more about how the influenza virus moves, grows and evolves. “We’re mainly interested in HA and NA, but there are other proteins, the M2 ion channel, membrane interactions, glycans, so many other possibilities,” Amaro stated.

“This also paves the way for other groups to apply similar methods to other viruses. We’ve modeled SARS-CoV-2 in the past and now H1N1, but there are other flu variants, MERS, RSV, HIV—this is just the beginning.”

More information: Lorenzo Casalino et al, Breathing and Tilting: Mesoscale Simulations Illuminate Influenza Glycoprotein Vulnerabilities, ACS Central Science (2022). DOI: 10.1021/acscentsci.2c00981

Journal information: ACS Central Science 

Provided by University of California – San Diego 

Scientists from Rice University are using fluorescence lifetime to shed new light on a peptide associated with Alzheimer’s disease, which the Centers for Disease Control and Prevention estimates will affect nearly 14 million people in the U.S. by 2060.

Through a new approach using time-resolved spectroscopy and computational chemistry, Angel Martí and his team found experimental evidence of an alternative binding site on amyloid-beta aggregates, opening the door to the development of new therapies for Alzheimer’s and other diseases associated with amyloid deposits.

The study is published in Chemical Science.

Amyloid plaque deposits in the brain are a main feature of Alzheimer’s. “Amyloid-beta is a peptide that aggregates in the brains of people that suffer from Alzheimer’s disease, forming these supramolecular nanoscale fibers, or fibrils” said Martí, a professor of chemistry, bioengineering, and materials science and nanoengineering and faculty director of the Rice Emerging Scholars Program. “Once they grow sufficiently, these fibrils precipitate and form what we call amyloid plaques.

“Understanding how molecules in general bind to amyloid-beta is particularly important not only for developing drugs that will bind with better affinity to its aggregates, but also for figuring out who the other players are that contribute to cerebral tissue toxicity,” he added.

The Martí group had previously identified a first binding site for amyloid-beta deposits by figuring out how metallic dye molecules were able to bind to pockets formed by the fibrils. The molecules’ ability to fluoresce, or emit light when excited under a spectroscope, indicated the presence of the binding site.

Time-resolved spectroscopy, which the lab utilized in its latest discovery, “is an experimental technique that looks at the time that molecules spend in an excited state,” Martí said. “We excite the molecule with light, the molecule absorbs the energy from the light photons and gets to an excited state, a more energetic state.”

This energized state is responsible for the fluorescent glow. “We can measure the time that molecules spend in the excited state, which is called lifetime, and then we use that information to evaluate the binding equilibrium of small molecules to amyloid-beta,” Martí said.

In addition to the second binding site, the lab and collaborators from the University of Miami uncovered that multiple fluorescent dyes not expected to bind to amyloid deposits in fact did.

“These findings are allowing us to create a map of binding sites in amyloid-beta and a record of the amino acid compositions required for the formation of binding pockets in amyloid-beta fibrils,” Martí said.

The fact that time-resolved spectroscopy is sensitive to the environment around the dye molecule enabled Martí to infer the presence of the second binding site. “When the molecule is free in solution, its fluorescence has a particular lifetime that is due to this environment. However, when the molecule is bound to the amyloid fibers, the microenvironment is different and as a consequence so is the fluorescence lifetime,” he explained. “For the molecule bound to amyloid fibers, we observed two different fluorescence lifetimes.

“The molecule was not binding to a unique site in the amyloid-beta but to two different sites. And that was extremely interesting because our previous studies only indicated one binding site. That happened because we were not able to see all the components with the technologies we were using previously,” he added.

The discovery prompted more experimentation. “We decided to look into this further using not only the probe we designed, but also other molecules that have been used for decades in inorganic photochemistry,” he said. “The idea was to find a negative control, a molecule that would not bind to amyloid-beta. But what we discovered was that these molecules that we were not expecting would bind to amyloid-beta at all actually did bind to it with decent affinity.”

Martí said the findings will also impact the study of “many diseases associated with other kinds of amyloids: Parkinson’s, amyotrophic lateral sclerosis (ALS), type 2 diabetes, systemic amyloidosis.”

Understanding the binding mechanisms of amyloid proteins is also useful for studying nonpathogenic amyloids and their potential applications in drug development and materials science.

“There are functional amyloids that our body and other organisms produce for different reasons that are not associated with diseases,” Martí said. “There are organisms that produce amyloids that have antibacterial effects. There are organisms that produce amyloids for structural purposes, to create barriers, and others that use amyloids for chemical storage. The study of nonpathogenic amyloids is an emerging area of science, so this is another path our findings can help develop.”

More information: Bo Jiang et al, Deconvoluting binding sites in amyloid nanofibrils using time-resolved spectroscopy, Chemical Science (2023). DOI: 10.1039/D2SC05418C

Journal information: Chemical Science 

Provided by Rice University