biomedicine – Lightsources.org

A New Framework for Designing Synthetic Enzymes

2026/04/272026/05/21

SCIENTIFIC ACHIEVEMENT

Researchers engineered protein-like polymers that replicate complex enzyme functions.

SIGNIFICANCE AND IMPACT

This work, which was verified using X-ray characterization techniques at the Advanced Light Source (ALS), offers a cost-effective, scalable approach that paves the way for functional materials in biomedicine, energy, and manufacturing

Schematic comparing the global folding patterns, chemical structures, and active sites of a) natural protein behavior demonstrating a rigid secondary structure of regular, local folding patterns in the chain of amino acids, stabilized by intramolecular bonding; and b) the protein-like polymers created in this study, which do not form secondary structures but instead adopt varying conformations based on the hydrophobic (water-repelling) properties of segments in the chain. Red, grey, blue and yellow correspond to very hydrophobic, hydrophobic, hydrophilic (water-loving) and very hydrophilic amino acid residues, respectively. The chemical structures of key functional residues are shown in the inset boxes. (Credit: Ting Xu/UC Berkeley/LBNL)

Protein-like functions, without the protein

Many industries already use enzymes, which are specialized protein molecules that accelerate chemical reactions without being consumed. Incorporating these catalytically active molecules into materials could unleash impactful applications biomedicine, energy generation, and chemical synthesis—including masks that eliminate airborne toxicants or environmental filters that degrade pollutants. Their practicality, however, is limited: naturally occurring enzymes tend to be fragile, costly, and unstable.

While these constraints have driven interest in synthetic polymers that mimic enzymatic activity, designing durable protein-like alternatives has been difficult. Natural enzymes rely on rigid secondary structures—local folding patterns along the amino acid chain—that determine whether a target molecule can bind at the active site and trigger a reaction. As a result, past efforts have generally assumed that precise sequence control was necessary to reproduce protein function. This has hindered industrial applications, as specifying the exact order of building blocks in a polymer chain requires costly, high-purity chemical reactions.

In this study, researchers reinterpreted proteins’ sequence-structure-function relationship to engineer polymers with bio-inspired functions and practical adjustments to their molecular chemistry. Using X-ray techniques at the ALS, the team connected how the polymers pack globally with how the local chemical microenvironments near the catalytic region shift upon target binding, a key factor governing function.

Read more on the ALS website

Breaking boundaries in biomedicine: APS enables protein design

2025/03/112025/04/28

From growth hormones to cancer drugs, small molecules play a crucial role in our health. Monitoring them is essential to keeping us healthy; it enables physicians to calculate dosages and patients to monitor their medical conditions at home, for example.

Monitoring small molecules depends on sensing where they are, and in what concentrations. While scientists have developed sensors to detect some small molecules, these sensors are used primarily in research and drug discovery and can only detect a limited range of molecules with particular qualities. There is a compelling need for sensors that can detect and signal the presence of diverse small molecules of different shapes, sizes, flexibility and polarity.

Using artificial intelligence (AI), a team of scientists led by Nobel Prize winner David Baker at the University of Washington has created a computational method for generating proteins that bind and signal a wide range of small molecules with great effectiveness. Baker won the 2024 Nobel Prize in Chemistry for computational protein design.

The research described here, published in Science and conducted in part at the Advanced Photon Source (APS), exemplifies that approach. The APS is a U.S. Department of Energy (DOE) Office of Science user facility at DOE’s Argonne National Laboratory.

The sensor design problem

Creating a protein sensor for small molecules is very difficult. The protein must first bind to the small molecule, then signal its presence.

The team solved both problems with modular design strategies. Their AI-generated proteins consist of identical repeating subunits surrounding a central cavity. The cavity holds a pocket where the small molecule binds.

The subunits, being modular, are easily disassembled. In this way, the small molecule binding proteins can be treated like Lego blocks and be connected to well-established signaling proteins (such as split green fluorescent protein, or GFP), to make a full sensing protein device. When a small molecule binds in the pocket, the subunits reassemble, which leads to the signaling module sending a signal that the small molecule is present.

First step: Binding

The team chose a diverse spectrum of ligands (molecules that bind to protein receptors to send signals between cells), including cholic acid, a biomarker for liver disease; methotrexate, a cancer drug, which requires regular monitoring; thyroxine, a human hormone that indicates thyroid conditions; and a cyclic peptide.

The scientists constructed a machine learning algorithm based on AlphaFold2 (a protein structure predictor whose developers, John Jumper and Demis Hassabis, shared the Nobel Prize in Chemistry with Baker) and other machine learning protein design algorithms to generate thousands of proteins to bind the small molecules.

After computational design, the team tested the designed proteins in the laboratory and identified binders to particular ligands, following computational design and using machine learning methods to choose the best designs for experimental tests.

To confirm the accuracy of their design approach, the Baker team turned to the APS. They used the ultrabright X-ray beams to collect data on the atomic structure of the binding proteins. Using the Northeastern Collaborative Access Team (NE-CAT) beamlines at 24-ID at the APS, the team determined the structures of crystals formed from one of the designed proteins.

“Prediction algorithms are excellent tools, but without verification of the structures, there’s no proof that the predictions match reality,” said Kay Perry of Cornell University, staff scientist at NE-CAT. “X-ray crystallography remains one of the best ways to make that confirmation, and the team was able to do so in this case.”

Second step: Signaling

The next challenge was turning the binding proteins into signaling proteins. The scientists took advantage of their modularity to create two different types of signaling events.

The team built ligand-induced dimerization proteins from the binders. Linna An, the first author of this study, said the technology can be used in many health-related applications, such as regulating the release of drugs in cancer therapies.

In a different type of signaling event, the scientists fused the binding proteins to a newly designed nanopore, a protein creating a channel allowing ion flow. The fused unit was constructed in such a way that when a small molecule blocked the binding pocket, the whole nanopore was blocked, preventing the flow of ions and loss of current. Loss of current signaled the presence of the small molecule.

Designed, pH-reversible synthetic protein cage

2024/12/202025/01/09

In this study published in Macromolecular Rapid Communications, a team of researchers from Centre for Programmable Biological Matter (Durham University), Malopolska Centre of Biotechnology and NSRC SOLARIS lead by prof. Jonathan Heddle designed a programmable artificial protein cage build from TRAP protein, that is sensitive to pH and can be disassembled on demand.

The rational design and production of a novel series of engineered protein cages are presented, which have emerged as versatile and adaptable platforms with significant applications in biomedicine. These protein cages are assembled from multiple protein subunits, and precise control over their interactions is crucial for regulating assembly and disassembly, such as the on-demand release of encapsulated therapeutic agents.

This approach employs a homo-undecameric, ring-shaped protein scaffold with strategically positioned metal binding sites. These engineered proteins can self-assemble into highly stable cages in the presence of cobalt or zinc ions. Furthermore, the cages can be disassembled on demand by employing external triggers such as chelating agents and changes in pH. Interestingly, for certain triggers, the disassembly process is reversible, allowing the cages to reassemble upon reversal or outcompeting of triggering conditions/agents.

This work offers a promising platform for the development of advanced drug delivery systems and other biomedical applications.

Read more on SOLARIS website

Image: Artistic representation of the designed protein cage geometry

Credit: Izabela Czernecka

A powerful tool for nanoparticles analysis in complex biological media

2024/11/212024/11/21

An article published by CNPEM researchers was featured on the Nano Letters scientific journal’s cover and explores how the X-ray Photon Correlation Spectroscopy (XPCS) technique can distinguish protein corona formation from nanoparticle aggregation in complex biological media.

The innovative work, carried out at Sirius, expands analysis capacity in nanomedicine and highlights the XPCS potential to characterize nanoparticle interactions in biological environments in real time, providing a valuable resource for nanobiotechnology research and new biomedical materials development.

The innovative nanoparticles applications in biomedicine

Nanoparticles are tiny structures, with dimensions generally between 1 and 100 nanometers. Due to its size, they can interact with cells, proteins and molecules in a highly precise way, which allows driven delivery of medicines and therapeutic agents. This allows, for example, for cancer treatments to be more effective, by releasing drugs directly into tumor cells, minimizing side effects on healthy tissues.

Furthermore, nanoparticles can be designed for responding to specific stimuli, such as pH, temperature or biological signs, allowing a controlled release of medicines only when necessary.

In the diagnosis area, nanoparticles offer new ways to prematurely detect diseases. They can be linked to specific biomarkers that bind to molecular targets, making it easier to identify cancerous cells or the presence of viruses and bacteria, for example.

The interaction between nanoparticles and proteins in biological systems

These applications, however, are conditioned to a predictable behavior of these nanoparticles in complex biological systems. In some cases, by coming into contact with biological fluids, such as blood, a protein coating can be formed around nanoparticles, a phenomenon known in biomedicine by the English term “protein corona”.

This happens because nanoparticles attract proteins present in the biological environment, forming a “corona” or “crown” around its surface. The formation of this protein corona strongly influences how do nanoparticles interact with cells and tissues in the organism, which can affect its efficacy and safety in medical applications, such as drug therapies, diagnostics, and vaccine development.

For these reasons, studying the protein corona formation and characteristics is crucial for the development of nanoparticles that are safe and effective for biomedical use.

Read more on LNLS website

Image: Schematic representation of a functionalized SiO2 nanoparticle

Novel protocol for mass production of nanowires

2021/12/022021/12/02

Nanotechnology is one of the major driving forces behind the technological revolution of this century and nanomaterials play a key role in this revolution. While the use of nanoparticles is widespread in industrial applications, the use of nanowires -wires with a diameter of only a few nanometres- is mostly reduced to scientific areas. The fields of biomedicine and permanent magnets would benefit from the cost-effective mass production of nanowires.

In a recent publication, researchers from the Universidad Complutense de Madrid (UCM) and various centres from the Consejo Superior de Investigaciones Científicas (CSIC), in collaboration with ALBA, have established a novel and sustainable synthesis protocol that allows obtaining a greater number of nanowires than conventional laboratory fabrication processes with considerably reduced production time and cost.

The goal of this project was to increase the production of metallic nanowires, reducing costs and timings to expand their applicability to industry. Due to the high costs associated with the high-purity aluminium normally used as the starting material, as well as with the low temperature and large anodization time, the commercial application of nanowires using anodized aluminium oxide is still limited by their fabrication process.