Tautomer
A tautomer is an alternative molecular form created by moving atoms and bonds, often involving hydrogen relocation and bond-order changes. Tautomers can share the same formula but differ in geometry, charge distribution, and interaction pattern.
A raw molecule can map to a tautomer set:
A canonicalization protocol chooses one representative:
Why It Matters
Tautomer handling changes deduplication, scaffold construction, conformer generation, docking, and property labels. A silent tautomer policy can make two pipelines look comparable when they are not.
Policy Choices
- Canonicalize: choose one deterministic representative for deduplication and splitting.
- Preserve: keep supplied tautomer states when the assay or structure supports them.
- Enumerate: generate a tautomer set and score or aggregate over it.
- Condition: choose tautomer state jointly with pH, protonation, binding site, or preparation protocol.
If a model uses one representative, the identity key should include the protocol:
where is the tautomer canonicalization policy.
Interaction With Protonation
Tautomer and protonation decisions are coupled:
Changing one can change hydrogen bonding, formal charge, conformers, and docking interactions.
Checks
- Is tautomer canonicalization applied before splitting?
- Is the chosen tautomer protocol recorded?
- Could the target distinguish tautomers biologically?
- Are 3D conformers generated after tautomer/protonation decisions?
- Are labels tied to a molecule definition that matches the model input?
- Does the featurizer cache key change when the tautomer policy changes?
Failure Modes
- Equivalent tautomer records appear on both sides of a split.
- Over-canonicalization removes a tautomer state that the target distinguishes.
- Docking uses a different tautomer/protonation state than the 2D featurizer.
- Generated molecules are evaluated before tautomer normalization, inflating novelty.
- Label aggregation silently averages measurements from different state definitions.