Proteins are nature’s master builders. Folded into intricate three-dimensional shapes, they can recognize one another, assemble into molecular machines, and organize themselves into structures ranging from viral shells to cellular scaffolds. Scientists have long hoped to harness this precision to create artificial materials with comparable complexity. Yet combining natural proteins with synthetic molecules remains difficult: the two components often lack broad, well-defined surfaces through which they can recognize and connect with one another. Researchers at Ludwig-Maximilians-Universität München (LMU) and collaborating institutions have now developed a molecular pairing that could provide a powerful solution.
The team, led by Professor Ivan Huc from LMU’s Department of Chemistry and Pharmacy, created an artificial protein–foldamer complex that functions as a modular connection point between biological and synthetic matter. Their results, published in Nature Chemistry, describe a protein scaffold that recognizes a specific synthetic molecule with high affinity and binds it across a large, precisely organized interface. Because the interaction is structurally defined rather than dependent on a flexible molecular tether, the pair can serve as a nanoscale building block for assembling more elaborate architectures.
The synthetic partner is a type of molecule known as a foldamer. Foldamers are designed to imitate one of the most important features of proteins: their ability to fold into stable, predetermined shapes. In this case, the foldamer adopts a helical structure. Like many helices, it can exist in two mirror-image forms, known as right-handed and left-handed helices. The researchers found that only the right-handed form, called the P-helix, was recognized by the selected protein. Its mirror image, the M-helix, showed no detectable binding, demonstrating an unusually high degree of molecular selectivity.
Finding a protein capable of recognizing the synthetic helix required searching through an enormous range of possible molecular structures. The researchers used ribosome display, a biochemical selection technology that can screen hundreds of billions of protein variants for a desired interaction. In this method, genetic information and the protein produced from it remain physically connected through a ribosome complex. When a protein variant binds a target molecule, scientists can recover the associated genetic code and use it to identify and reproduce the best candidates. Although ribosome display was originally developed mainly to study protein–protein recognition, the LMU-led team showed that it can also identify interactions between proteins and artificial foldamers.
After four rounds of selection, the researchers identified a protein variant known as C10. It belongs to a compact protein scaffold called Nanofitin, which is designed to remain stable while presenting a surface capable of molecular recognition. C10 bound the P-helix with substantial strength and formed an extensive contact area with it. Such a broad interface is important because it distributes the binding energy across many individual contacts, including hydrogen bonds, hydrophobic interactions and shape complementarity. Together, these interactions can produce a connection that is both strong and geometrically reliable.
The researchers used several complementary methods to determine how the two components fit together. Nuclear magnetic resonance spectroscopy provided information about the molecules in solution, including changes in their local chemical environments when binding occurred. X-ray crystallography then revealed the arrangement of atoms in the assembled complex in the solid state. Mass spectrometry was used to analyze larger assemblies and determine how many proteins and foldamers were associated with one another. The combined data showed that the protein and foldamer form a stable supramolecular “synthon”—a recurring molecular association that can be used as a transferable construction unit.
With the interaction understood, the team began testing how the pair could be used to build larger structures. By modifying the foldamer, the researchers created a molecule capable of binding two physically separated copies of the protein. The reverse design was also possible: protein dimers could be configured so that each protein component recognized a separate foldamer. These arrangements convert the original protein–foldamer pair into a programmable connector. Instead of merely producing one stable complex, scientists can use the binding geometry to control how multiple components are positioned relative to one another.
The approach produced several striking architectures. In crystals, the building blocks assembled into ring-shaped structures and into one-dimensional zigzag networks. The exact geometry of these assemblies depended on the dimensions and arrangement of the connecting molecules. Changing the length of the foldamer altered the distance between bound proteins and influenced their spatial orientation. This kind of control is crucial for nanotechnology, where a difference of only a few nanometers can determine whether neighboring components interact, remain separate or form a continuous network.
Computer-aided analysis of the crystal lattice suggested that some of the resulting materials are highly porous. The largest cavities in the modeled structures could theoretically accommodate spherical objects approximately five nanometers in diameter, a size range that includes certain nanoparticles and large biomolecules. Although these calculations do not by themselves establish a practical material for filtration, catalysis or delivery, they point toward possible applications in which protein-based frameworks provide internal spaces for capturing or organizing other nanoscale objects.
The researchers say the new protein–foldamer pair could eventually support the construction of artificial three-dimensional materials with precisely arranged biological components. Because the foldamer’s length and chemical composition can be modified, it may be possible to adjust the spacing between proteins or introduce additional functional groups into the resulting network. The same strategy could also be applied to naturally occurring proteins. By equipping selected proteins with foldamer-binding domains, scientists might use synthetic helices to bring them together, hold them at defined distances or alter how they communicate with one another. Such control could open new routes to programmable biomaterials, molecular catalysts and hybrid nanostructures that combine the adaptability of biology with the chemical versatility of synthetic design.
Subject of Research:
A protein–foldamer molecular building block for constructing hybrid nanostructures and porous artificial materials.
Article Title:
A protein–foldamer supramolecular synthon for self-assembled hybrid architectures
News Publication Date:
17 August 2026
Web References:
https://doi.org/10.1038/s41557-026-02222-6
References:
Nature Chemistry, “A protein–foldamer supramolecular synthon for self-assembled hybrid architectures,” DOI: 10.1038/s41557-026-02222-6.
Keywords:
Protein engineering, foldamers, supramolecular chemistry, nanostructures, ribosome display, Nanofitin, self-assembly, hybrid materials, molecular recognition, porous materials
