Stop Collapsing Conformation Space
Most “structure-aware” ML methods still reason from a single chosen pose.
That move is computationally convenient. It’s also chemically wrong.
The mistake: collapsing the manifold before the model sees it
A small molecule is not a single 3D object. It’s a distribution over conformations.
Binding, permeability, and intramolecular H-bonding depend on the family of shapes the molecule can realistically occupy.
When you pick one pose and call it “the structure,” you erase the actual variable you’re trying to reason about.
Why this matters beyond docking
Even if you never run a docking campaign, conformation drives:
- exposed polar surface area vs shielded PSA
- effective flexibility penalties
- the presence/absence of productive IMHB patterns
- scaffold topology differences across analogues
If your workflow treats 3D as a thumbnail, you will keep getting surprised by “obvious” failures.
The Blaise stance: conformer ensembles are first-class
With Blaise AI, you can generate conformer ensembles and interrogate the conformation space interactively.
Not as an afterthought, but as a core object:
- compare ensemble properties across a congeneric series
- spot conformational locks and torsional bottlenecks
- reason about shape families, not single snapshots
A practical mental model
Think of a molecule as living on a manifold.
Your job isn’t to find the pose.
Your job is to understand:
- which regions of the manifold are populated
- which are accessible under realistic conditions
- how substitutions move probability mass around the manifold
That’s the kind of reasoning medicinal chemists already do informally.
Blaise makes it explicit and actionable.