Building Protein-Like Helices from Non-Natural Amino Acids for the First Time | Research

The takeaway

Scientists created the first high-resolution structure of an artificial peptide helix built entirely from non-natural amino acid building blocks, mimicking the shape of natural protein helices.

First high-resolution 13-helix structure
Confirmed by both X-ray crystallography and 2D NMR — proving beta/gamma-peptides can form defined helical folds without any natural amino acids

What the researchers found

The researchers provided the first high-resolution structural data for the beta/gamma-peptide 13-helix — a secondary structure formed by oligomers with a 1:1 alternation of beta- and gamma-amino acid residues. The structure was confirmed by both X-ray crystallography and 2D NMR spectroscopy.

The 13-helix features i,i+3 C=O...H-N hydrogen bonds, creating a folding pattern analogous to the alpha-helix found in natural proteins but built entirely without natural alpha-amino acids. The key to achieving this fold was using preorganized (conformationally constrained) beta- and gamma-residues, which strongly promote 13-helical folding. Previous studies with conformationally flexible residues had resulted in different helical structures.

Why it matters

One of the biggest challenges in peptide drug development is that natural peptides are rapidly chewed up by enzymes in the body. Foldamers — artificial peptides built from non-natural building blocks — resist these enzymes because the body's proteases don't recognize their unusual backbone chemistry. But for foldamers to be useful as drugs, they need to fold into defined shapes that can interact with biological targets. This study proves that beta/gamma-peptides can form stable, well-defined helices, making them promising scaffolds for designing enzyme-resistant peptide therapeutics.

The numbers in context

13-helix structure · 1:1 beta/gamma amino acid alternation · i,i+3 hydrogen bonding pattern · X-ray crystallography + 2D NMR confirmation

How the study worked

This was a synthetic chemistry and structural biology study. The researchers designed and synthesized beta/gamma-peptide sequences using preorganized (conformationally constrained) amino acid residues with alternating beta and gamma building blocks. They characterized the three-dimensional structure using two complementary high-resolution methods: X-ray crystallography (to determine the solid-state structure) and 2D NMR spectroscopy (to confirm the structure exists in solution).

Who was studied

Not applicable (synthetic chemistry and structural characterization study)

What this study cannot tell us

This is a pure structural chemistry study with no biological activity data — the foldamers were not tested against any biological target. Only short oligomers were characterized, and it's unclear how longer sequences would behave. The preorganized residues required for stable folding add synthetic complexity that could limit practical applications. No in vivo studies were conducted.

How to read the evidence

Rated 'strong' for a structural chemistry study because it provides the first high-resolution data using two complementary methods (X-ray and NMR), published in the Journal of the American Chemical Society by a leading foldamer research group.

When this study was published

Published in 2010 in JACS. This is a foundational study in foldamer chemistry that has been widely cited and built upon. The design principles established here continue to inform peptide drug design.

The bigger picture

This work is part of the broader foldamer research field, which aims to create artificial molecules that mimic the structures and functions of natural proteins. The ability to build stable helices from non-natural amino acids opens the door to designing peptide-like drugs that resist degradation, can be taken orally, and have longer half-lives in the body. The Gellman lab has been a leader in this field, and this structural milestone helps establish the design rules for an entire class of potential therapeutics.

Questions still open

Can beta/gamma-peptide 13-helices be designed to interact with specific protein targets, mimicking the function of natural alpha-helical peptides?
How do these foldamers behave in biological environments — are they truly resistant to proteolytic degradation as expected?
Can the preorganized building blocks be manufactured at scale for drug development applications?

Common questions

What is a foldamer and why does it matter for drug design?

A foldamer is an artificial molecule that folds into a defined three-dimensional shape, similar to how natural proteins fold. They're built from non-natural building blocks (like beta- and gamma-amino acids) that the body's enzymes can't easily break down. If foldamers can mimic the shapes of natural protein structures, they could serve as more durable versions of peptide drugs.

What's the difference between alpha, beta, and gamma amino acids?

Natural proteins are built from alpha-amino acids, which have one carbon between the amino and acid groups. Beta-amino acids have two carbons, and gamma-amino acids have three. These extra carbons change the backbone geometry, making the resulting peptides invisible to the body's protein-digesting enzymes — a major advantage for drug design, though it requires careful engineering to get them to fold properly.

Read the original research

Helix formation in preorganized beta/gamma-peptide foldamers: hydrogen-bond analogy to the alpha-helix without alpha-amino acid residues.

Journal of the American Chemical Society, 132(23), 7868-9

View on PubMed ↗Publisher’s paper ↗

Citation

Guo, Li; Almeida, Aaron M; Zhang, Weicheng; Reidenbach, Andrew G; Choi, Soo Hyuk; Guzei, Ilia A; Gellman, Samuel H. (2010). Helix formation in preorganized beta/gamma-peptide foldamers: hydrogen-bond analogy to the alpha-helix without alpha-amino acid residues.. Journal of the American Chemical Society, 132(23), 7868-9. https://doi.org/10.1021/ja103233a