Metalloion−Ligand Binding Energies and Biological Function of Metalloenzymes Such as Carbonic Anhydrase. A Study Based on ab Initio Calculations and Experimental Ion−Ligand Equilibria in the Gas Phase
Bibliographic record
Abstract
The known structure of carbonic anhydrase includes the structure of the active site, which consists of Zn 2+, coordinated to three histidine (His) residues and a water molecule. The ligand involved in the catalysis is the water molecule. Using imidazole (Im) to model histidine, it is found that histidine is the strongest bonding residue to Zn 2+ of all neutral amino acid residues. On the basis of high-level ab initio calculations, the sequential bond energies for one to three imidazoles attached to Zn 2+ were evaluated. The bond energy Zn(Im) 3 2+ −(H 2 O) was also determined by ab initio calculations and (gas phase) ion equilibria measurements. From a comparison of the free energy of stabilization of Zn 2+ in the enzyme and that in aqueous solution, we conclude that very strongly bonding residues such as histidine are essential to make the Zn 2+ ion in the enzyme stable, relative to the aqueous environment. The strongly bonding histidine also has another more important role. Due to the very large charge transfer and polarizability energy component with such a ligand and ligand−ligand repulsion, the bonding to the fourth, i.e., the H 2 O ligand, is very much weakened. It is shown that weakening of the Zn(L) 3 2+ −(H 2 O) bond energy is unfavorable, i.e., increases the energy required for the first step of the accepted mechanism, Zn(His) 3 OH 2 2+ → Zn(His) 3 OH + + H +, while the second step, Zn(His) 3 OH + + CO 2 Zn(His) 3 (H 2 O) 2+ + HCO 3 -, is favorably affected, i.e., requires less energy. The choice of the ligands L therefore must be such so as to lead to a compromise between the two opposing effects. By making a semiquantitative inclusion of the solvent effect of the protein and aqueous environment on the reaction free energies for the above two ionic reactions, it was possible to show that the “choice” of the three histidine ligands is “just right” to provide this compromise. These ligands lead to reaction free energies that are close to zero for both reactions.
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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 | 0.000 | 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 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".