Computational Insights into Amide Bond Formation Catalyzed by the Condensation Domain of Nonribosomal Peptide Synthetases
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Bibliographic record
Abstract
High Resolution Image Download MS PowerPoint Slide Nonribosomal peptide synthetases (NRPSs) are important enzymes that synthesize an array of nongenetically encoded peptides. The latter have diverse physicochemical properties and roles. NRPSs are modular enzymes in which, for example, the condensation (C-) domain catalyzes the formation of amide bonds. The NRPS tyrocidine synthetase from Brevibacillus brevis is responsible for synthesizing the cyclic-peptide antibiotic tyrocidine. The first step is formation of an amide bond between a proline and phenylalanine which is catalyzed by a C-domain. In this study, a multiscale computational approach (molecular dynamics and QM/MM) has been used to investigate substrate binding and catalytic mechanism of the C-domain of tyrocidine synthetase. Overall, the mechanism is found to proceed through three exergonic steps in which an active site Histidine, His222, acts as a base and acid. First, His222 acts as a base to facilitate nucleophilic attack of the prolyl nitrogen at the phenylalanyl’s carbonyl carbon. This is also the rate-limiting step with a free energy barrier of 38.8 kJ mol –1 . The second step is collapse of the resulting tetrahedral intermediate with cleavage of the S–C bond between the phenylalanyl and its Ppant arm, along with formation of the above amide bond. Meanwhile, the now protonated His222 imidazole has rotated toward the newly formed thiolate of the Ppant arm. In the final step, His222 acts as an acid, protonating the thiolate and regenerating a neutral His222. The overall mechanism is found to be exergonic with the final product complex being 46.3 kJ mol –1 lower in energy than the initial reactant complex.
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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) | 0.000 | 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) | 0.000 | 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