Cheminformatics

Boltzmann-Expected Molecular Design with Decoupled Annealing Flows

Selma Moqvist, Richard Beckmann, Ross Irwin, Rocío Mercado, Simon Olsson

Featured July 28, 2026

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Simply

Instead of designing molecules based on just one shape, this method creates molecules by considering all their possible jiggling shapes, allowing it to design for flexibility and specific average properties.

In depth

DECAF introduces Boltzmann-expected molecular design, optimizing molecular graphs for properties averaged over their full 3D conformational ensembles, rather than single structures. It achieves this by decoupling the generative process into a Boltzmann emulator for 3D coordinates and a graph proposer, which are then iteratively optimized using a simulated annealing approach guided by ensemble statistics.

Key Takeaways

1
DECAF enables ensemble-aware molecular design by optimizing properties averaged over the Boltzmann distribution, addressing limitations of single-conformer models.
2
The framework decouples graph generation from conformational sampling using two conditional flow models: a Boltzmann emulator $p_{θ} (x ∣ G)$ and a graph proposer $p_{θ} (G ∣ x)$ .
3
It uniquely supports higher-moment design, allowing optimization of properties like variance and skewness of conformational distributions, beyond just the mean.

Conceptual Flow

HIGH LEVEL

Designing Molecules with All Their Shapes

The method learns to create molecule shapes from a given structure and also to suggest new structures from a given shape, then uses these two skills to find the best molecules.

Molecule Structure

Molecule Shape

Learn to Connect

Better Molecule Structure

Better Molecule Shape

Beyond Just Average Size

The new method successfully changes not just the average size and surface area of molecules, but also how much their size varies and if they prefer compact or stretched shapes.

Old Molecule Shapes

Change Properties

New Molecule Shapes

Controlled Flexibility

Desired Compactness