Self-assembly of a foldamer-protein 1D polymer
Scientific Frontline: Extended "At a Glance" Summary: Protein-Foldamer Supramolecular Synthons
The Core Concept: Researchers have developed a molecular building block that utilizes an artificial protein-foldamer pair to combine proteins and synthetic molecules with high structural precision, forming complex nanostructures.
Key Distinction/Mechanism: Unlike previous protein-foldamer complexes that were less stable or required flexible connectors, this new system uses a specific protein variant (Nanofitin C10) that binds to an artificial foldamer (a stable, helical molecule) with high affinity over a large, well-defined contact surface. It selectively binds the right-handed P-helix of the foldamer, but not the left-handed M-helix.
Major Frameworks/Components:
- Foldamer: An artificial molecule that folds into a stable shape (a helix).
- Nanofitin C10: A protein scaffold variant identified through ribosome display.
- Ribosome Display: A biochemical method used to identify protein-protein (and in this case, foldamer-protein) interactions from hundreds of billions of variants.
- Analytical Techniques: Nuclear magnetic resonance (NMR) spectroscopy, X-ray crystallography, and mass spectrometry were used to analyze the structural fit and larger complexes.
Branch of Science: Chemistry, Biochemistry, Nanotechnology, and Structural Biology.
Future Application: The building blocks can be used to construct porous three-dimensional materials with customizable properties by altering the length and chemical composition of the foldamers. The resulting highly porous crystal lattices could theoretically encapsulate nanoparticles or large molecules. Additionally, this technology could be used to arrange naturally occurring proteins to influence their biological functions.
Why It Matters: Arranging proteins and synthetic molecules with structural precision has traditionally been difficult due to the lack of clear contact surfaces. This modular building block solves that problem, enabling the targeted creation of complex, functional molecular architectures and novel artificial materials.
Proteins form complex three-dimensional shapes and can join together to create larger structures. Researchers want to use these properties to make artificial materials. However, arranging proteins and synthetic molecules together with a high level of structural precision is no easy task. This is partly due to the lack of large, clearly defined contact surfaces between the two components.
Researchers led by Professor Ivan Huc from the Department of Chemistry and Pharmacy at LMU have teamed up with colleagues from Berlin, Bordeaux, and Nantes to develop an artificial protein-foldamer pair that meets this requirement. “A specifically selected protein recognizes a synthetic molecule and binds to it with high affinity,” summarizes Huc. “The sizable contact surface, which has a clearly defined structure, makes it possible to use the complex as a modular building block for larger molecular architectures.” The team has now presented the results in the journal Nature Chemistry.
The Search for the Right Counterpart
This new paper focuses on a foldamer, an artificial molecule that, similar to a protein, folds into a stable shape—in this case, a helix.
The researchers were looking for a protein that would be the exact counterpart for this foldamer. In their research, they used ribosome display, a biochemical method for identifying protein-protein interactions from hundreds of billions of different protein variants; this method also proved effective for foldamer-protein interactions. After four rounds of selection, the team identified variant C10 of a protein scaffold known as Nanofitin.
The right-handed P-helix of the foldamer binds C10 with great strength, whereas no binding was detected for the left-handed M-helix. The protein and foldamer are in contact with each other over a large, clearly defined area. Previous protein-foldamer complexes were less stable or required flexible connectors.
From a Molecule to a Network
The team investigated how the protein and foldamer structurally fit together using nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography, among other techniques. The researchers also analyzed larger complexes using mass spectrometry.
They then used these binding pairs to create more complex structures. A foldamer constructed in this way was able to bind two proteins physically separate from one another. Conversely, it was possible to configure protein dimers in such a way that they were able to bind two foldamers.
In addition, ring-shaped architectures and a one-dimensional, zigzag network were created in crystals. The arrangement can be influenced via the geometry of the building blocks. The length of the foldamer determines, for example, the spacing and the spatial orientation of the bound proteins.
Computer-aided analyses of the crystal lattice show a high porosity. The largest cavities could theoretically accommodate spherical objects—for example, nanoparticles or large molecules—with a diameter of around 5 nanometers.
Prospects of Producing Artificial Materials
“Our results show that artificial foldamers can be used as precise connecting elements for protein architectures,” says Huc. “Because it is possible to change their length and chemical composition, they could in the future play a role in helping to construct porous three-dimensional materials and introduce additional functional groups into such structures in the process.”
The specific arrangement of naturally occurring proteins presents another potential topic for new studies. If these proteins are equipped with foldamer-binding domains, foldamers could bring them together or maintain a defined spacing between them, possibly influencing their biological function as a result.
Published in journal: Nature Chemistry
Title: A protein–foldamer supramolecular synthon for self-assembled hybrid architectures
Authors: Johannes Sigl, Vasily Morozov, Lingfei Wang, Janine Sachs, Eric Merlet, Eric Largy, Niklas Geue, Nicklas Österlund, Sunbum Kwon, Florian Sanchez, Léo Candela, Simon Huet, Kevin Pagel, Yann Ferrand, Céline Douat, Cameron D. Mackereth, and Ivan Huc
Source/Credit: Ludwig-Maximilians-Universität München
Edited by: Scientific Frontline
Reference Number: chm081826_01
