Illustrative model calculation
Averaging the rates can change which chemistry you choose.
Consider two illustrative barrier profiles. Candidate A has four equally weighted conformers at 18, 21, 24 and 27 kcal/mol. Candidate B stays at 20 kcal/mol. Ranking their mean barriers favors B. Averaging each conformer's rate contribution at 310.15 K instead gives A an effective barrier of about 18.85 kcal/mol, below B's 20. The low-barrier conformer changes the decision.
- A or B?Supply barriers and weights
A: 18 / 21 / 24 / 27. B: 20 throughout. Equal populations.
- 22.5 → 18.85Average rates for A
Mean barrier → effective barrier, in kcal/mol. B remains at 20.
- Ranking reversesTest the conformer dependence
Check whether A's low-barrier population survives better sampling and calibration.
- What changes from the baseline · The comparison is with exponentiating the mean barrier. Established ensemble kinetics also averages rates; the useful output here is a visible explanation of which conformers control the candidate comparison.
- The next synthesis decision · Before favoring A, check the low-barrier geometry, its weight and the reaction method. If the ordering depends on an uncertain conformer, resolve that uncertainty before expanding the chemical series. Constrained scans still need transition-state and rate-calibration checks.
| Candidate | Mean barrier | Rate-averaged effective barrier | Decision consequence |
|---|---|---|---|
| A: four equally weighted conformers | 22.5 kcal/mol | 18.85 kcal/mol | Faster predicted rate when the low-barrier conformer contributes. |
| B: barrier fixed at 20 kcal/mol | 20.0 kcal/mol | 20.0 kcal/mol | Preferred only by the mean-barrier comparison in this example. |
Illustrative calculations at 310.15 K with the same rate prefactor. Barriers and populations are assumed; no measured candidate performance is compared.
Compare the series under the same assumptions
Single-geometry calculations offer a useful reference. The ensemble approach asks whether the relative rates change across conformers and how weighting those conformers affects the ranking. Consistent methods and convergence checks matter as much as the apparent difference between candidates.
A relative ranking with a defined scope
The toolkit contains barrier and rate-calibration methods for computational investigation. Constrained energy scans need further checks before they can be interpreted as verified transition states. A stable ranking does not by itself establish absolute reaction rates.
Connect accessibility to reactivity carefully
Ensemble ligandability can identify conformations worth examining; reaction calculations can ask what chemistry they support. That connection requires compatible structures and weights. It should be tested as a composition rather than assumed from the two methods’ availability.
- Boltzmann ensemble ligandability · Examine joint access and cysteine-chemistry questions. Boltzmann ensemble ligandability
- Target-specific covalent design · Compare recognition, reaction conditions and exposure to prioritize candidate designs and their next laboratory tests. Target-specific covalent design
Choose the experiment that calibrates the ranking
Use a defined chemical series with measured reaction rates. Check whether the ranking survives plausible sampling and method changes before making it the basis for a larger synthesis campaign.