Intramolecular Hydrogen Bond-Controlled Prolyl Amide Isomerization in Glucosyl 3(<i>S</i>)-Hydroxy-5-hydroxymethylproline Hybrids: A Computational Study
Bibliographic record
Abstract
Peptide mimics containing spirocyclic glucosyl-(3(S)-hydroxy-5(S)-hydroxymethyl)proline (1) and glucosyl-(3(S)-hydroxy-5(R)-hydroxymethyl)proline (2) hybrids differing in the stereochemistry of the polar hydroxymethyl substitutent at the C-5- or (C(delta))-position have been investigated computationally. A computational "build and search" protocol of molecular mechanics systematic search/Monte Carlo search, followed by density functional theory (DFT), has been developed to ensure complete coverage of the large conformational space. Gas-phase DFT optimizations at the B3LYP level of theory lead to a strong preference for the cis conformation in the prolyl amide bond for both compounds 1 and 2. However, inclusion of the solvent water by means of continuum solvation (PCM) results in a reduction of the prolyl amide cis population in both compounds, leading to good agreement with previous experimental observations. Intramolecular hydrogen bonding involving the C-5-hydroxymethyl substitutent is seen to play a crucial role to tune the thermodynamics of prolyl amide cis/trans isomerization and is responsible for the high cis prolyl amide population in compound 2. Our results indicate that H-bond-forming substituents like the hydroxymethyl group at the C-5-position in proline can be used to control cis/trans prolyl amide isomerization. High cis prolyl amide conformer populations can be achieved by proper choice of the stereochemistry at the C-5-position.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".