Programmable Helicity and Macrocycle Symmetry in β-Peptides via Site-Selective Thioamide Substitution
Bibliographic record
Abstract
High Resolution Image Download MS PowerPoint Slide Thioamides─minimalist amide isosteres in which sulfur replaces the backbone carbonyl oxygen─offer a precise means to modulate peptide conformation through altered hydrogen-bond geometry and polarity. This work presents a general and experimentally validated strategy for programming β-peptide secondary structure with atomic precision, using site-selective thioamide substitution as a minimalist backbone modification. While thioamides have been studied individually, their positional control within β-peptides to direct helicity, curvature, and topology has not been achieved before. Using trans -2-aminocyclopentanecarboxylic acid (ACPC) foldamers as a model system, we show that strategic thioamide placement enables hybrid 12/8-helices, backbone-encoded curvature, and conical 16/12-helices; symmetry-defined macrocycles (pseudo- C 2, pseudo- C 3, pseudo- C 4 ) inaccessible by conventional β-peptide synthesis; gram-scale, solution-phase synthesis of β-peptides up to 32-mers (>4 kDa), the longest reported to date; and orthogonal editing via mild Ag(I)-mediated backbone conversion to all-amide analogs in 97–99% yield, allowing folding to be programmed with temporary thioamide units before conversion to the desired scaffold. These advances establish a unified framework for controlling β-peptide helicity and topology through minimal backbone editing, significantly expanding the accessible structural and functional space for foldamer chemistry. The concepts and methodologies are broadly applicable to organic synthesis, supramolecular chemistry, biomolecular engineering, and peptide-inspired materials.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".