Molecular Basis of Chiral Acid Recognition by <i>Candida rugosa</i> Lipase: X‐Ray Structure of Transition State Analog and Modeling of the Hydrolysis of Methyl 2‐Methoxy‐2‐phenylacetate
Why this work is in the frame
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Bibliographic record
Abstract
Abstract Lipase from Candida rugosa shows high enantioselectivity toward α‐substituted chiral acids such as 2‐arylpropionic acids. To understand how Candida rugosa lipase (CRL) distinguishes between enantiomers of chiral acids, we determined the X‐ray crystal structure of a transition‐state analog covalently linked to CRL. CRL shows moderate enantioselectivity ( E =23) toward methyl 2‐methoxy‐2‐phenylacetate, 1 ‐methyl ester, favoring the ( S )‐enantiomer. We synthesized phosphonate ( R C , R P S P )‐ 3 , which, upon reaction with CRL, mimics the transition state for hydrolysis of ( S )‐ 1 ‐methyl ester, the fast‐reacting enantiomer. An X‐ray crystal structure of this complex shows a catalytically productive orientation with the phenyl ring in the hydrophobic tunnel of the lipase. Phe345 crowds the region near the substrate stereocenter. Computer modeling of the slow‐reacting enantiomer examined four possible conformations for the corresponding slow‐reacting enantiomer: three conformations where two substituents at the stereocenter have been exchanged relative to the fast‐reacting enantiomer and one conformation with an umbrella‐like inversion orientation. Each of these orientations disrupts the orientation of the catalytic histidine, but the molecular basis for disruption differs in each case showing that multiple mechanisms are required for high enantioselectivity.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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) | 0.000 | 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 it