Intramolecular Hydrogen Bond-Controlled Prolyl Amide Isomerization in Glucosyl 3′(<i>S</i>)-Hydroxy-5′-hydroxymethylproline Hybrids: Influence of a <i>C</i>-5′-Hydroxymethyl Substituent on the Thermodynamics and Kinetics of Prolyl Amide <i>Cis</i>/<i>Trans</i> Isomerization
Bibliographic record
Abstract
Peptide mimics containing spirocyclic glucosyl-(3'-hydroxy-5'-hydroxymethyl)proline hybrids (Glc3'(S)-5'(CH(2)OH)HypHs) with a polar hydroxymethyl substituent at the C-5' position, such as C-terminal ester Ac-Glc3'(S)-5'(CH(2)OH)Hyp-OMe and C-terminal amide Ac-Glc3'(S)-5'(CH(2)OH)Hyp-N'-CH(3), were synthesized. C-Terminal esters exhibit increased cis population (23-53%) relative to Ac-3(S)HyPro-OMe (17%) or Ac-Pro-OMe (14%) in D(2)O. The prolyl amide cis population is further increased to 38-74% in the C-terminal amide form in D(2)O. Our study shows that the stereochemistry of the hydroxymethyl substituent at the C-5' position of proline permits tuning of the prolyl amide cis/trans isomer ratio. Inversion-magnetization transfer NMR experiments indicate that the stereochemistry of the hydroxymethyl substituent has a dramatic effect on the kinetics of prolyl amide cis/trans isomerization. A 200-fold difference in the trans-to-cis (k(tc)) isomerization and a 90-fold rate difference in the cis-to-trans (k(ct)) isomerization is observed between epimeric C-5' 3 and 4. When compared to reference peptide mimics Ac-Pro-OMe and Ac-3(S)Hyp-OMe, our study demonstrates that a (13-16)-fold decrease in k(tc) and k(ct) is observed for the C-5'(S), while a (5-24)-fold acceleration is observed for the C-5'(R) epimer. DFT calculations indicate that the pyrrolidine ring prefers a C(beta) exo pucker in both Ac-Glc3'(S)-5'(CH(2)OH)Hyp-OMe diastereoisomers. Computational calculations and chemical shift temperature coefficient (Delta delta/Delta T) experiments indicate that the hydroxymethyl group at C-5' in Ac-Glc3'(S)-5'(CH(2)OH)Hyp-OMe forms a stabilizing intramolecular hydrogen bond to the carbonyl of the N-acetyl group in both epimeric cis isomers. However, a competing intramolecular hydrogen bond between the hydroxymethyl groups in the pyrrolidine ring and pyran ring stabilizes the trans isomer in the C-5'(S) diastereoisomer. The dramatic differences in the kinetic properties of the diastereoisomeric peptide mimics are rationalized by the presence or absence of an intramolecular hydrogen bond between the hydroxymethyl substituent located at C-5' and the developing lone pair on the nitrogen atom of the N-acetyl group in the transition state.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".