Crafting New Molecules to Mimic Nature's Blueprint
In the quest to mimic nature's architectural genius, scientists are creating a new class of molecules that could revolutionize medicine and materials science.
Proteins are the workhorses of biology, folding into intricate three-dimensional shapes that dictate their function. For decades, scientists have attempted to create synthetic molecules that mimic these natural structures—a pursuit that has given rise to the field of foldamer research. These artificial chains of molecules fold into predictable, ordered structures just like proteins and nucleic acids, but with advantages that could transform medicine and technology 8 .
Among the most sought-after designs are right-handed helical foldamers that replicate the characteristic twists of natural protein helices. The challenge is formidable: creating new molecular scaffolds that are both structurally robust and functionally versatile. Recently, a breakthrough emerged from the intersection of chemistry and design—a new class of foldamers consisting of de novo D-AApeptides that reliably form right-handed helical structures, opening unprecedented possibilities for biomedicine and materials science 3 7 .
Foldamers are discrete chain molecules (oligomers) that fold into conformationally ordered states in solution, stabilized by noncovalent interactions between nonadjacent monomers 8 . They represent a bridge between synthetic chemistry and biology, allowing researchers to create molecules that mimic the folding behavior of proteins, nucleic acids, and polysaccharides without being limited to nature's building blocks.
Synthetic molecules that mimic protein structures and functions.
Designed to imitate nucleic acid interactions and properties.
Stabilized by aromatic and charge-transfer interactions not commonly found in nature 8 .
The ability to predict and control foldamer structure based on their primary sequence represents a fundamental advance, potentially enabling scientists to design large molecules with predictable structures for specific applications.
In nature, many crucial protein elements form right-handed helices, particularly the α-helix, a common protein secondary structure. Creating synthetic molecules that reliably adopt this specific handedness has been a significant hurdle, especially when incorporating D-amino acids, which typically favor left-handed helical conformations due to their intrinsic opposite folding propensity 3 .
This challenge is more than academic—the handedness (chirality) of a molecule directly impacts its biological activity and interactions. Many biological systems can distinguish between mirror-image molecules, making controlled handedness essential for therapeutic applications.
Previous attempts to create hybrid foldamers combining L- and D-amino acids produced unpredictable results, with folding propensities difficult to anticipate due to competing structural preferences 3 .
Typical for D-amino acids
Target for biomimicry
In 2017, researcher Jianfeng Cai and team reported a surprising discovery: heterogeneous oligomers incorporating D-sulfono-γ-AApeptides that consistently fold into well-defined right-handed helices 3 7 9 . This finding was particularly unexpected because D-peptides typically adopt left-handed helical conformations.
The team designed sequences with a 2:1 pattern of L-amino acids to D-sulfono-γ-AA residues, creating hybrid molecules that blend natural and synthetic components 3 . Through sophisticated structural analysis, they demonstrated that these oligomers fold into what they termed a "4.5â‚₆–â‚â‚„ helix"—a novel helical structure with unique parameters distinct from natural protein helices.
The unique folding pattern discovered in these hybrid foldamers represents a new class of helical structure with distinctive characteristics:
This hydrogen bonding pattern involves three distinct types of interactions: between the N-H group of an α-amino acid and the C=O group of an α-amino acid four residues earlier (16-atom ring), between the N-H group of an α-amino acid and the C=O group of a D-sulfono-γ-AA four residues earlier (16-atom ring), and between the N-H group of a D-sulfono-γ-AA and the C=O group of a D-sulfono-γ-AA four residues later (14-atom ring) 3 .
| Secondary Structure | Handedness | Helical Pitch (Ã…) | Radius (Ã…) | Residues per Turn |
|---|---|---|---|---|
| 4.5â‚₆–â‚â‚„ Helix | Right-handed | 5.1 | 2.6 | 4.5 |
| α-Helix | Right-handed | 5.4 | 2.3 | 3.6 |
| 3â‚â‚€ Helix | Right-handed | 6.0 | 1.9 | 3.0 |
| π-Helix | Right-handed | 5.0 | 2.8 | 4.4 |
Data adapted from single-crystal X-ray crystallography studies 3
The groundbreaking discovery of right-handed helical foldamers emerged from meticulous design and state-of-the-art structural analysis. The research team employed a systematic approach to demonstrate these novel structures definitively.
Researchers designed oligomers with repeating units of L-Phe, L-Ala, and 4-chlorobenzenesulfonyl-containing D-sulfono-γ-AA residues in a 2:1 ratio pattern 3 . This specific arrangement was hypothesized to promote the novel folding behavior.
Using Fmoc chemistry on solid support, the team synthesized four sequences of varying lengths. The reactions proceeded efficiently without requiring acetic anhydride capping after each coupling cycle 3 .
The researchers obtained high-quality crystals of the foldamers through slow evaporation from solvent systems including acetonitrile (with 0.5% trifluoroacetic acid) and acetonitrile/THF/water mixtures 3 .
Using single-crystal X-ray crystallography with remarkable resolutions (0.83-1.12 Ã…), the team solved the three-dimensional structures of multiple oligomers, providing atomic-level detail of the novel helix 3 .
The crystal structures were validated using 2D NMR studies, circular dichroism (CD), and molecular dynamics simulations, confirming that the observed folding behavior persisted in solution 3 .
The structural data revealed several surprising findings:
| Residue Type | Backbone Torsion Angles | Values (Degrees) | Comparison to Natural Structures |
|---|---|---|---|
| α-Ala Units | φ', ψ' | -62±3, -39±7 | Similar to α-helices (-64±7, -41±7) |
| α-Phe Units | ϕ″, ψ″ | -108±4, 125±9 | Closer to β-strands (-130±10, 125±10) |
| D-sulfono-γ-AA | Multiple angles | Unique values | Differ from all natural structures |
Data derived from high-resolution crystallography studies 3
This experiment provided the first high-resolution three-dimensional structures to guide the design of D-sulfono-γ-AApeptides, which had never been thoroughly studied before due to the lack of structural information 3 7 . The findings established a new paradigm for designing foldamers with controlled handedness, an essential requirement for biological applications.
Creating and studying foldamers requires specialized reagents and techniques. Here are key components of the foldamer researcher's toolkit:
| Reagent/Technique | Function in Foldamer Research | Specific Examples from D-AApeptide Studies |
|---|---|---|
| D-sulfono-γ-AA Building Blocks | Synthetic amino acid derivatives that enable novel folding behaviors | 4-chlorobenzenesulfonyl-containing D-sulfono-γ-AA residues 3 |
| Solid-Phase Synthesis | Method for systematically constructing oligomer sequences | Fmoc chemistry on solid support without need for acetic anhydride capping 3 |
| Single-Crystal X-ray Crystallography | Determining atomic-resolution 3D structures of foldamers | Structures solved at 0.83-1.12 Ã… resolution 3 |
| 2D NMR Spectroscopy | Studying foldamer conformation and dynamics in solution | Validation of helical structures in solution 3 |
| Circular Dichroism (CD) | Assessing helical content and handedness in solution | Confirmation of right-handed helical structures 3 |
| Molecular Dynamics Simulations | Theoretical modeling of folding behavior and stability | Validation of structural models and folding dynamics 3 |
The development of predictable right-handed helical foldamers opens exciting possibilities across multiple disciplines:
Foldamers offer enhanced resistance to proteolytic degradation compared to natural peptides, making them promising candidates for therapeutic development 3 . Their sequence diversity and customizable structures enable the design of molecules that can specifically interact with challenging targets like protein-protein interactions, which have been difficult to address with conventional small molecules 5 .
As our understanding of foldamer design principles improves, these synthetic molecules may complement natural biopolymers in engineered biological systems, expanding the chemical diversity available for creating artificial life forms or biological devices.
Recent advances continue to build on these foundations. Studies published in 2025 explore strategies for controlling foldamer conformation through methods like stapling and demonstrate their application in molecular recognition 1 6 . The ongoing refinement of computational models promises to accelerate the design of foldamers with customized structures and functions .
The discovery of right-handed helical foldamers consisting of de novo D-AApeptides represents more than a technical achievement—it exemplifies a fundamental shift in our approach to molecular design. By understanding and mimicking nature's principles while expanding beyond its building block limitations, scientists are creating a new generation of molecules with tailored structures and functions.
As research progresses, these designed foldamers may lead to breakthroughs in drug development, materials science, and biotechnology. The ability to control molecular handedness with precision opens pathways to more effective therapeutics and advanced materials that interface seamlessly with biological systems. The future of foldamer research promises not just to mimic nature's elegance but to expand its possibilities, creating molecular architectures that transcend what evolution has produced thus far.